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Rose Bengal Binding to Collagen and Tissue Photobonding

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† Division of Cardiac Surgery, University of Ottawa Heart Institute, 40 Ruskin Street, K1Y 4W7 Ottawa, ON, Canada
‡ Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, K1H 8M5 Ottawa, ON, Canada
§ Center for Bioinformatics and Molecular Simulation, Universidad de Talca, 2 Norte 685, Casilla 721, Talca 3460000, Chile
∥ Institute of Computational Comparative Medicine, Nanotechnology Innovation Center of Kansas State, and Department of Anatomy and Physiology, Kansas State University, Manhattan, Kansas 66503, United States
⊥ Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, 40 Blossom Street, Boston, Massachusetts 02114, United States
*E-mail: [email protected] (E.I.A.).
*E-mail: [email protected] (J.C.).
Cite this: ACS Omega 2017, 2, 10, 6646–6657
Publication Date (Web):October 11, 2017
https://doi.org/10.1021/acsomega.7b00675

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Abstract

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We investigated two critical aspects of rose Bengal (RB) photosensitized protein cross-linking that may underlie recently developed medical applications. Our studies focused on the binding of RB to collagen by physical interaction and the effect of this binding and certain amino acids on RB photochemistry. Molecular dynamics simulations and free-energy calculation techniques, complemented with isothermal titration calorimetry, provided insight into the binding between RB and a collagen-like peptide (CLP) at the atomic level. Electrostatic interactions dominated, which is consistent with the finding that RB bound equally well to triple helical and single chain collagen. The binding free energy ranged from −5.7 to −3 kcal/mol and was strongest near the positively charged amino groups at the N-terminus and on lysine side chains. At high RB concentration, a maximum of 16 ± 3 bound dye molecules per peptide was found, which is consistent with spectroscopic evidence for aggregated RB bound to collagen or the CLP. Within a tissue-mimetic collagen matrix, RB photobleached rapidly, probably due to electron transfer to certain protein amino acids, as was demonstrated in solutions of free RB and arginine. In the presence of arginine and low oxygen concentrations, a product absorbing at 510 nm formed, presumably due to dehalogenation after electron transfer to RB. In the collagen matrix without arginine, the dye generated singlet oxygen as well as the 510 nm product. These results provide the first evidence of the effects of a tissue-like environment on the photochemical mechanisms of rose Bengal.

1 Introduction

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Novel medical treatments are currently being developed based on the photosensitized formation of protein–protein cross-links using rose Bengal (RB), a member of the xanthene family of dyes. For example, sutureless wound sealing is achieved by applying RB to the wound surfaces, followed by a short green light irradiation. This application is known as photochemical tissue bonding or PTB. A major advantage of PTB is the minimal scarring and fibrosis produced compared to that from suturing. (1-7) Photosensitized protein cross-linking also prevents deleterious changes to tissue in response to physiological pressures. (8-11) Rose Bengal photosensitization also makes tissue less prone to inflammation, known as photochemical tissue passivation. (12) Despite the increasing number of medical uses of RB-mediated protein cross-linking, the underlying molecular mechanisms remain largely unknown.
The photochemistry and photophysics of rose Bengal have been investigated extensively in aqueous solution. (13, 14) At pH 7.0, RB has an absorption maximum of 550 nm with a shoulder at 525 nm, a fluorescence quantum yield of 0.02, and a triplet quantum yield of 0.75. (14, 15) Rose Bengal is often used to generate singlet oxygen (1O2), which has been suggested to mediate formation of protein–protein bonds. (16, 17) In addition, both reductive and oxidative quenching of the RB triplet state are favorable with many electron donors and acceptors. In aqueous solution at pH 7.0, the one electron reduction potential is 1.09 V (vs standard calomel electrode (SCE)) and the oxidation potential is −0.78 V (vs SCE). (18) The rose Bengal anion radical forms dehalogenated and/or dihydro products. (14, 18-20) However, RB forms dimers and higher multimers in aqueous solution that show substantially reduced photochemical reactivity. (21-24)
The in vivo molecular environment in tissues is expected to strongly influence the photochemical reactions of rose Bengal because the dye binds to proteins including collagen, human serum albumin, and silk fibroin. (22, 25, 26) Our previous studies using a combination of changes in absorption spectra of RB and molecular dynamics revealed the formation of rose Bengal–collagen ground state complexes. (22) The dye–collagen complexes show a red-shifted absorption maximum at 560 nm, a lower fluorescence yield, and a reduced rate of photodegradation. Interestingly, similar spectral changes are observed when rose Bengal is applied to tissues. (7, 8) Ground state association between RB and proteins within the tissue limits the dye mobility, which might reduce triplet excited state quenching. In addition, in tissue, the oxygen supply is lower than that in air, thus reducing 1O2 formation and potentially favoring electron transfer processes for protein cross-linking.
Our long-range goal is to increase the efficiency of PTB to extend its range of medical applications. As steps to reach this goal, we have carried out studies on two fundamental aspects of rose Bengal photosensitized protein cross-linking, namely, (1) the binding of rose Bengal to collagen and collagen matrices, and (2) the influence of collagen, certain amino acids, and oxygen on rose Bengal photochemistry.
We used absorption spectroscopy and isothermal calorimetry to characterize the association of RB as a monomer and as aggregates to collagen, to a small collagen-like peptide (CLP), and to a three-dimensional (3D) tissue-mimetic collagen matrix. Molecular dynamics simulations were used to identify energetically favorable molecular and atomic level interactions involved in the binding. The influence of certain amino acids and collagen on RB photodecomposition was examined in solution and in the collagen matrices using absorption spectroscopy and nanosecond transient absorption spectroscopy.

2 Results

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2.1 Association of Rose Bengal with Collagen and a Collagen-Like Peptide

Collagen (type I) is the major structural protein in the connective tissues, for example, the skin, cornea, and tendon, and tissue repair using PTB is believed to result from cross-links between collagens. To begin to understand the association of RB with collagen, we examined whether the normal triple helical collagen conformation was required, investigated the interaction of RB with a tissue-mimetic collagen matrix, and also measured the exothermicity of the association. A more detailed molecular level picture of the RB–collagen association complexes was then gained from molecular dynamics simulations.

2.1.1 RB–Collagen Association in Solution: Absorption Spectroscopy and Isothermal Titration Calorimetry

In a previous study of the association of rose Bengal with type I collagen in solution, we observed a shift in the RB absorption spectrum that, along with molecular dynamics simulation calculations, indicated the presence of RB aggregates bound to triple helical collagen. (22) To determine whether the triple helical structure is required for association with RB, absorption spectra of 10 μM RB in the presence of varying concentrations of either native (triple helical) or thermally denatured, that is, single-stranded, type I collagen were measured. The RB spectra with 2.5 μM native or denatured collagen (Figure S1a,b) showed no statistical difference, see Figure S1c. Although association of RB with denatured collagen produced an approximately 2 nm greater red shift in the absorption maximum, Figure S1d,e. Circular dichroism experiments for rose Bengal measured at a ratio of 4:1 (rose Bengal/collagen) showed optically active features in the 520–600 nm region (Figure S2a), which is a further indication of the ground state association.
Experiments carried out at a lower dye concentration, 1.25 μM, and decreasing collagen concentrations showed that the initial shift in the absorption spectrum is present at a low ratio of 1:2 RB/collagen and becomes more distinct at higher dye loading with a broadening of the absorption spectra (Figure S2b). Over this concentration range, RB fluorescence decreased with a 50% lower fluorescence for the rose Bengal/collagen ratio of 0.5 (Figure S2c).
To examine the association between RB and single chain collagen in a simpler system, absorption spectra were recorded in the presence of varying concentrations of a collagen-like peptide (CLP) that contains high proportions of glycine (G), proline (P), and hydroxyproline (O), similar to the composition of collagen (≈81% homology; CG(PKG)4(POG)4(DOG)4), and was also used for the simulations described below. As the concentration of CLP increased, the RB absorption maximum at 550 nm shifted to longer wavelengths (≈570 nm) and decreased in amplitude to an even greater degree than that observed in the presence of collagen (Figure 1a). Higher concentrations of CLP (230 μM, see Figure 1b) were required to produce the maximal change in RB absorption maximum compared to that of collagen (≈1.25 μM, see Figure S1c).

Figure 1

Figure 1. Effect of collagen-like peptide on 10 μM rose Bengal absorption. (a) Spectral changes and (b) changes in the absorption at RB monomer maximum 550 nm and at 570 nm, the maximum of the red-shifted peak for aggregated RB bound to CLP, plotted as a function of CLP concentration. All measurements were carried out in 10 mM MES buffer (pH 5.0).

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We then studied the calorimetry for the binding of rose Bengal to the CLP. Figure S3a shows the enthalpy changes resulting from addition of increasing concentrations of CLP to a dye solution. At peptide concentrations larger than 200 μM, there was a plateau in the enthalpy, which can be interpreted as the endothermic assembling of the single unit peptide into a triple helix supramolecular structure. Next, we evaluated the changes in enthalpy for the binding of rose Bengal to CLP at concentrations at which the peptide is assembled (450 μM, Figure S3b). The enthalpy of formation for the RB–CLP complex is exothermic, in the range of −10 ± 2 kcal/mol, which roughly agrees with the free energies estimated by molecular simulations, vide infra.
We had initially attempted to measure heat changes for the association of RB to type I collagen by adding RB to collagen solutions. However, even adding even small quantities of the dye led to precipitation of collagen (not shown). Independent experiments measuring the protein surface charge, ζ potential measurements, for solutions of collagen showed a 50% decrease of the protein charge upon association of the dye Figure S4.

2.1.2 Rose Bengal Association with Collagen Matrices

To investigate the binding of RB to collagen in a more tissue-like environment, we generated 3D collagen hydrogel matrices and evaluated the RB absorption spectra for three different RB concentrations (5, 10, and 40 μM; Figure S5). Control experiments indicated that the denaturation temperature of the matrices with and without the dye (54 ± 2 °C, not shown) did not show a statistical difference. Rose Bengal within the collagen matrix has a maximum absorption centered at 555 nm, similar to that for collagen in solution (Figure 2). The relative absorptions at 525 and 550 nm for 40 μM RB in collagen hydrogels (right panel) were comparable to that seen for 1000 μM RB in solution (left panel), indicating that the RB concentration for aggregation was lower in the collagen hydrogels.

Figure 2

Figure 2. Right: Normalized absorption spectra for RB prepared at different dye concentrations incorporated within collagen matrices. Left: Normalized absorption spectra for RB measured in buffer solutions. All measurements were carried out in phosphate buffer pH 7.4 at room temperature.

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2.1.3 Molecular Dynamics Simulations of RB–Collagen Association

To determine the nature of RB binding to the CLP at the atomic level that might provide information for modeling RB protein photo-cross-linking in tissue, we carried out molecular dynamics simulations. The structure of the CLP triple helix was modeled based on an experimentally derived collagen structure. (27) RB was modeled with the predominant protonation state for pH > 4.3, (22) with −2 charges (Figure 3a). The simulation system is illustrated in Figure 3b. The resulting affinity free-energy map is shown in Figure 3c. Owing to electrostatic interactions, the RB molecule appears to be attracted to the positively charged N-terminus (including three NH3+ groups) and the 12 Lys residues containing NH3+ on their side chain in the N-terminal region of the CLP. It is repelled from the negatively charged C-terminus (including three carboxylate groups) and the 12 carboxylate-containing Asp residues present near this terminus. A minimum of free energy of −5.7 kcal/mol appears at the N-terminus. A prominent local minimum with a free energy of −5.5 kcal/mol occurs about 7 Å further along the CLP axis, in the region of the CLP containing Lys residues. Another local minimum occurs nearer to the center of the peptide, at the interface between the region containing Lys residues and that containing Hyp residues, having a depth of −3.4 kcal/mol.

Figure 3

Figure 3. Molecular simulation of RB binding to the CLP. (a) Molecular model of RB in the charge state used in the simulations. The carboxylate and phenolate moieties each have charges of −1. Atom color code: H, white; C, cyan; O, red; Cl, green; I, purple. (b) Snapshot of a simulation of the CLP triple helix with one molecule of RB. The CLP is shown as a green tube, Na+ and Cl– ions are shown as yellow and cyan spheres. For clarity, the explicit water molecules are shown as a transparent surface. (c) Free-energy landscape for RB in the vicinity of the CLP triple helix at low RB concentration, calculated by the adaptive biasing force method. The potential of mean force is mapped as a function of the position of the RB molecule along the CLP axis (disZ) and distance from this axis (disXY). The geometric contribution to the free energy along disXY has been removed. (d) Free-energy landscape at a higher RB concentration calculated from a set of equilibrium simulations including a CLP triple helix and 20 RB molecules. (e) Snapshot from the simulation with 20 RB molecules.

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The free-energy landscape shown in Figure 3c was calculated with only a single RB molecule in the system and, therefore, estimates the free energy in the limit of low RB concentration. To better understand the affinity of RB for the CLP at the higher RB concentrations that are used in vivo for PTB, we performed five independent equilibrium simulations in systems containing 20 RB molecules. Averaging over the last 200 ns of the five independent simulations (1000 ns in length), we found 16 ± 3 (mean ± SD) molecules within 6 Å of the center of mass of the CLP. The free-energy landscape is shown in Figure 3d along with a snapshot from one of the simulations in Figure 3e. Despite its negative charge, RB formed aggregates both in contact with the CLP and in free solution. Note that in Figure 3d, the electrostatic shielding due to the presence of many RB molecules reduces the affinity at the N-terminus, leading to relatively uniform strong binding over the N-terminal half of the CLP.
We then sought to determine the atomic-scale interactions that underlie the RB affinity of different regions of the peptide model. The highest affinity was seen at the N-terminus where the N-terminal NH3+ groups and NH3+-containing Lys side chains make contact with the negatively charged groups of RB. Figure 4a shows an exemplary snapshot including an ionic interaction and H-bond between an N-terminus and the carboxylate moiety of RB. Although a majority of configurations associated with the global free-energy minimum included ionic contacts, a few, such as that in Figure 4b, exhibited no close contact between charged groups. We find no water molecules between the three-ring motif of RB and the Pro side chains, indicating that hydrophobic collapse may drive RB binding, in addition to longer-range electrostatic interactions. Farther from the N-terminus, binding of RB was dominated by ionic contacts with the NH3+ of Lys residues, an example of which is shown in Figure 4c. It might be noted that considerable nonplanarity of the three-ring motif of RB is sometimes observed when the phenolate O– atom of RB makes contact with NH3+ groups, as in Figure 4c. A local free-energy minimum at (disXY, disZ) = (10.1, −17.9 Å) appears to correspond to contact between the phenolate O– atom of RB and NH3+ of Lys residues of the collagen-like peptide, as well as H-bonding between the carboxylate of RB and OH groups of Hyp (Figure 4d). The locations of the configurations in Figure 4a–d on the free-energy landscape are indicated in Figure 4e, along with the approximate locations of CLP side chains relevant for binding RB.

Figure 4

Figure 4. Molecular interactions between RB and CLP. (a) Electrostatic contact and H-bonding between the N-terminus of the CLP and the carboxylate group of RB. In these images, the phenolate (O–) group is highlighted by a red sphere to distinguish it from the carbonyl oxygen. Atoms are colored as in Figure 3, except that CLP carbons are colored dark green. H-bonds are indicated by dotted black lines. (b) Hydrophobic contact between the three-ring moiety of RB and a Pro residue of the CLP. (c) H-bonding between the O– group of RB and the backbone NH of the CLP, coupled with ionic contact between the O– group and a Lys side chain. (d) H-bonding between the OH group of hydroxyproline (Hyp) and the carboxylate group of RB. An ionic Lys–O– contact is also apparent. (e) The free-energy landscape of RB near the CLP with labels (a–d) indicating the location of RB in the corresponding panels of this figure. The ranges of disZ values occupied by the N-terminus and Asp, Hyp, and Lys side chains are also indicated. (f) The prevalence of H-bonding between RB and different groups of the CLP as a function of position along the CLP axis. Plotted are the number of H-bonds involving all CLP groups (CLP), backbone amide nitrogens (BB), N-terminal NH3+ groups (Nter), Hyp side chain OH groups, and Lys side chain NH3+ groups. (g) The prevalence of H-bonding between the CLP and different groups of RB as a function of position along the CLP axis.

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The prevalence of H-bonds between RB and various groups of the collagen-like peptide are quantified in Figure 4f,g. The most H-bonding occurs at and near the N-terminus, with the dominant contribution from N-terminal and Lys NH3+ donors (Figure 4f). Comparison to Figure 4g demonstrates that these N-terminal H-bonds predominantly involve the carboxylate and phenolate oxygens of RB. Near disZ = −40 Å, H-bonds involving the backbone of the CLP or the carbonyl oxygen of RB are also present. In the region of the CLP for disZ > 10 Å, few H-bonds are observed, and instead it is dominated by contacts between the carboxylate group of RB and the OH groups of the Hyp residues of CLP (exemplified in Figure 4d).
In the experiments, it was noted that a small fraction of the peptide did not form the conventional collagen triple helix, but remained free in solution. This motivated us to simulate a single collagen-like peptide chain together with a high concentration of the dye (20 molecules) to understand the binding mode of RB when the peptide does not form a triple helix. We found that the peptide adopted an ensemble of disordered compact structures, which contrasted with the well-defined linear arrangement of the triple helix. However, formation of RB aggregates both close to the peptide and in solution was observed. Averaging over the last 10 ns of an independent simulation (100 ns in length), we found 8 ± 1 (mean ± SD) molecules within 5 Å of the peptide (not shown).

2.2 Photochemical and Photophysical Behavior of Rose Bengal in Solution and 3D Collagen Matrix

In our previous study, the RB photodegradation rate was lower in collagen-containing solutions, (22) indicating that the dye photoreactivity in tissue might be influenced by its association with collagen. To begin to understand the RB photochemistry that initiates collagen cross-linking, we studied the dye photodegradation at high concentrations in aqueous solution where aggregates dominate, roughly mimicking the aggregrates formed with collagen. These results were compared to RB photodegradation at low concentrations, where mainly monomeric species are present, in solutions containing collagen, and in the 3D collagen hydrogels. We also evaluated the effects of certain amino acids on RB excited triplet state lifetime and photodegradation in solutions and hydrogels to further characterize potential pathways initiating protein cross-linking.

2.2.1 Photodecomposition of Rose Bengal Alone in Solution

The absorption spectrum of 125 μM RB in phosphate-buffered saline (PBS) showed the typical absorption maximum at 550 nm with a ratio of absorption at 550–520 nm as approximately 2, an indication that rose Bengal exists as dimers and aggregates at this concentration. (28, 29) Monomeric RB shows a ratio of approximately 3. In O2 and air, the absorbance at 550 nm decreased without a change in the spectral shape and product(s) absorbing at approximately 450 nm formed (Figure S6a,b). In a N2 atmosphere, the RB absorption decreased with a slight broadening of the 550 nm peak to longer wavelengths and without formation of a 450 nm absorbing product (Figure S6b). Photodecomposition was less efficient in N2, as shown by the greater RB absorption at the end of the irradiation period.

2.2.2 Influence of Arginine, Lysine, and Ascorbic Acid on Rose Bengal Photodegradation in Solution

Arginine and lysine are potential electron donors to the rose Bengal triplet state and, because they are positively charged at pH 7, are present in collagen chains at reasonable levels; they are also likely to be association sites for RB with collagen, as indicated by the simulations described above. Irradiations carried out on 125 μM RB solutions containing 25 mM Arg showed that the dye photodegraded more rapidly in N2-saturated compared to O2-saturated solutions. Significantly, the absorption maximum under N2 blue-shifted to 510 nm (Figure 5a), which is consistent with the formation of a deiodinated fluorescein product that would be formed after initial electron transfer to the RB excited triplet state. (19, 20) In an air atmosphere, only a 10 nm red shift was observed, and in O2-saturated solutions, total photobleaching occurred without an absorption maximum shift (Figure 5b).

Figure 5

Figure 5. Photodecomposition of rose Bengal (125 μM) in the presence of arginine (25 mM). (a) Irradiation of rose Bengal in nitrogen saturated solution. (b) Absorption spectra (expanded scale) of rose Bengal samples irradiated for 7 min in the presence of 25 mM Arg in solutions saturated with oxygen, air, and nitrogen. All data collected in PBS buffer pH 7.4 at room temperature. Solutions irradiated at 532 nm, irradiance = 0.3 W/cm2. Results shown are from single irradiations in triplicate independent experiments.

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A similar set of irradiations carried out using 25 mM Lys had little effect on RB photodecomposition, except under N2 where it decreased the degradation rate by about 3.5 fold. Ascorbate (1.25 mM), another biological electron donor, increased the RB photodegradation rate in air and N2 atmospheres compared to the dye alone, and the absorption maximum shifted toward a 510 nm absorbing product (Figure S7).
The photobleaching rate for monomeric rose Bengal (10 μM) was greater under N2 than in an air-saturated solution (Figure 6a), the opposite of that found for RB aggregates. However, similar to what is seen for the rose Bengal aggregates, Arg enhanced the dye photodegradation. Azide blocked the RB photodegradation in air, which suggests singlet oxygen mediated dye degradation, and carrying out the irradiation in deuterium oxide buffer had little effect initially but appeared to increase the RB photodecomposition after 15 min irradiation, which may suggest participation of singlet oxygen in the photodecomposition mechanism.

Figure 6

Figure 6. Photodegradation of 10 μM RB in the presence of different additives: (a) without and (b) with 2.5 μM collagen at RB/collagen (4:1). Left: Absorption spectra for RB measured in solution at different irradiation times. Right: Changes in absorption intensities measured at 550 nm, plotted as A/A0, for RB solutions recorded in the presence of different additives. All data collected in 10 mM MES buffer pH 5.0 at room temperature. Data correspond to the average calculated from three independent experiments each repeated in triplicate (n = 9).

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2.2.2.1 Transient Absorption Measurements in Solution
Because we have now shown that arginine enhances the rate of rose Bengal photodecomposition, we asked whether this might result from direct interaction of the RB excited triplet state with Arg. The triplet decays for rose Bengal at 620 nm in the absence and presence of 0.5 mM Arg showed quenching with a rate constant of 0.17 × 108 M–1 s–1. The tryptophan quenching rate constant for rose Bengal triplet was considerably higher than that for Arg (3.0 × 108 M–1 s–1) in the same buffer system, see Figure S8, which is consistent with our previous report. (18) No RB triplet state was observed when the solutions contained 2.5 μM collagen, the conditions under which RB appears to be entirely bound as aggregates to collagen.

2.2.3 Photodegradation of Rose Bengal in Collagen Solutions

To examine the effect of binding to collagen on RB photodegradation, we irradiated solutions containing 2.5 μM native type I collagen and 10 μM RB. As shown in Figure 6b, the absorption spectrum indicated that the dye was aggregated in association with collagen as previously reported. (22) Photodegradation was enhanced by Arg (18%), D2O as solvent (17%), and by changing the atmosphere to N2 (15%). Percentages were calculated from following the changes in absorption intensity.

2.2.4 Photodegradation of Rose Bengal in Collagen Hydrogel Matrices

In the tissue-like environment of hydrogels prepared from native type I porcine collagen, RB was irradiated at pH 7.4 with a green LED centered at 525 nm. As shown in Figure 7(left), the RB absorption maximum is ≈556 nm as found for solutions of dye and collagen. Irradiation in an air atmosphere decreased the dye absorption and shifted the absorption maximum to the blue, which is similar to the changes observed during irradiation of aggregated RB in the presence of Arg (Figure 5), and indicates formation of deiodinated products. Figure 7 (right panel) shows the relative absorption at 556 nm as a function of irradiation time. Arginine (10 mM) enhanced the rate of RB degradation in a similar manner to the result obtained for the dye without collagen. Azide and tryptophan inhibited dye photodegradation.

Figure 7

Figure 7. Photodegradation of 40 μM RB incorporated within collagen hydrogels prepared using type I collagen containing different additives. Left: Absorption spectra for the RB–collagen hydrogel composite measured at different irradiation times in an air atmosphere. Right: Changes in absorption intensities measured at 556 nm for RB solutions recorded in the presence of different additives [Azide: 10 mM, Trp: 2 mM, Arg: 10 mM]. All data collected in PBS buffer pH 7.4 at room temperature. Data correspond to the average calculated from three independent experiments each repeated in triplicate (n = 9).

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2.2.5 Transient Absorption Measurements in Collagen Matrices

An investigation of the RB-derived transient species in the hydrogels showed the presence of a short-lived dye triplet (620 nm absorption maximum; lifetime = 3.5–4.0 μs; Figure 8a), which is significantly shorter than that in the collagen-free solutions (∼100 μs, see Figure S8). Thus, in the matrices, the triplet lifetime appears to be limited by competitive processes such as electron transfer to the protein or intra-aggregate excitation decay routes. The rose Bengal triplet lifetime was not influenced by tryptophan although Arg and azide both significantly quenched the RB triplet (Figure 8b). The RB anion radical was detected at 420 nm, which is consistent with electron transfer from collagen or ground state RB. It was quenched by O2 and partially quenched by Arg, Trp, and azide (Figure 8c). Interestingly, 1O2 luminescence at 1270 nm was detected for oxygenated samples, and this emission was readily quenched by sodium azide (Figure 8d), a well-known charge transfer deactivator for singlet oxygen. (30)

Figure 8

Figure 8. Triplet transient lifetime and quenching of RB embedded in collagen hydrogels in the presence of different quenchers. (a) RB triplet decay monitored at 620 nm measured in air (black circles) or nitrogen (blue circles) saturated solutions. Insets correspond to decay residuals obtained from the exponential fit for the decays shown in the figure. Measured lifetimes for: (b) RB triplet, (c) RB anion radical, and (d) singlet oxygen under different conditions or additives. Concentrations of additives were: tryptophan: 2.0 mM, Arg: 10 mM, and sodium azide: 10 mM. Effect of additives for laser flash photolysis experiments were carried out in nitrogen saturated solutions. For singlet oxygen measurements, samples were equilibrated with air prior to laser excitation. Measurements for triplet and anion radical were carried out in 10 mM pH 5.0 MES buffer. For singlet oxygen phosphorescence, a 10 mM MES buffer was prepared with a pD of 5.0. In all cases, photodegradation was kept lower than 10%. Time traces correspond to the average of 12 separate decays from 3 independent samples.

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2.2.6 Tryptophan-Mediated Photodegradation in Rose Bengal Containing Collagen Matrices

To further assess the photoreactivity of RB in collagen matrices, we studied its ability to promote degradation of tryptophan. Collagen matrices containing RB were incubated with 2.0 mM Trp and then exposed to the green LED. Changes in Trp fluorescence intensity at 370 nm upon excitation at 295 nm are shown in Figure S9. In the absence of Trp, no emission was detected. Figure S9a shows a fast decrease for the Trp emission intensity within the first 5 min of irradiation, which then remains largely unchanged (see Figure S9b). To assess the contribution of rose Bengal photoproducts toward the generation of photochemically active species, we pre-irradiated a set of samples of RB–collagen matrices for 30 min and we then incubated those samples with Trp followed by green light irradiation, see Figure S9b. For those samples, the emission values remained within experimental error, and practically unchanged when compared to time 0.

3 Discussion

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The results of these investigations suggest a first approximation of the processes involved in PTB for tissue healing. In this model, aggregates of rose Bengal bind to tissue collagen at positively charged amino acids and less avidly by hydrophobic forces at other sites. Triplet excited state RB accepts an electron from arginine side chains and possibly other sources when the O2 level is low. Subsequent reactions of the RB anion radical or arginine cation radical may initiate protein cross-linking. At higher O2 levels, cross-linking may be initiated by reactions of 1O2.
The two-dimensional free-energy landscapes as a function of distance along the triple helix and the distance from this axis shown in Figure 3, revealed two strong electrostatic interactions with energies from −5.7 to −3 kcal/mol between the two negative charges of rose Bengal and positively charged amino groups of the three N-termini and of the 12 Lys amino acids, visible in the lower half of Figure 4e. These electrostatic interactions are possible for both single chain and triple helical collagen, and explain our observation that RB binding to native and denatured collagen was nearly identical (Figure S1). In addition to the electrostatic binding modes for the association, hydrophobic interactions between the three-ring portion of the dye structure and Pro side chains were seen (Figure 4c). Notably, a nonplanarity of the three-ring motif was also observed. This distortion in the ring planarity can be linked to changes in electronic density and uniformity of the dye molecular orbitals, which leads to perturbations in the dye absorption spectrum fingerprinting at 525 nm.
Multioccupation or cooperative binding of rose Bengal to collagen is a plausible explanation for the formation of rose Bengal aggregates with collagen. (31) In fact, the multioccupation/cooperative binding of rose Bengal to the collagen structure, which results in a net change of protein surface charge, explains our unsuccessful attempts to carry out ITC by adding dye to collagen that resulted in precipitation of the protein due to changes in the protein charge (Figure S4). ITC measurements carried out for the CLP indicate that assembly of the peptide into a triplet helix occurs at >200 μM, see Figure S3, which is in good agreement with the data collected for binding of rose Bengal to CLP, see Figure 1. Consistent with the molecular dynamics simulations, association of rose Bengal to the peptide showed exothermic behavior, with values close to the calculated values (Figures 3 and 4). Similarly, for the experiments embedding rose Bengal within the collagen matrix, the presence of molecular aggregates was evident at 40 μM of dye, a concentration that does not show the presence of aggregates in aqueous solutions, see Figure 2.
The binding of rose Bengal to collagen differs from its previously reported association with other proteins. For example, binding in pockets on human serum albumin produced a similar red shift in the RB absorption spectrum. However, a 7-fold increase in the RB fluorescence emission was observed, (25, 31) whereas collagen binding produced a decrease in the dye fluorescence, see Figure S2c. For albumin–RB, the increase in emission was attributed to the transfer of the dye to a confined environment, wherein hydrogen bonding with water was no longer favored. For rose Bengal and collagen, the binding modes described for the CLP might lead to a more effective nonradiative deactivation, that is, intracomplex electron transfer, and consequently decreased fluorescence intensity. The collagen structure differs substantially from that for albumin. The triple helices are closely packed into fibrils that do not allow RB molecules to enter the fibril. Consequently, binding of rose Bengal to collagen in tissues occurs on the outer collagen fibril surfaces and involves the associations described by the molecular dynamics simulations.
Although almost all previous studies of RB photochemistry in aqueous solution have focused on monomeric RB, we investigated aggregated as well as monomeric rose Bengal because an ∼1.0 mM solution is used for medical applications and, at this high concentration, the dye exists as aggregates. In fact, the absorption spectrum of rose Bengal applied to cornea showed the red-shifted absorption spectrum and the <2 ratio of absorbance at 560–525 nm characteristic of aggregates bound to collagen. (8, 22)
Rose Bengal photochemistry in aggregates has differences and similarities with that for monomeric RB. For example, although both aggregated and monomeric RB photobleach in O2 without a spectral shift, only aggregated RB forms product(s) absorbing around 450 nm (Figure S6). These products may involve adjacent RB molecules in the aggregate, although their identity awaits further investigation. The mechanism for RB photobleaching in O2 also appears to differ. Irradiation of monomeric rose Bengal generates 1O2, which then oxidizes the xanthone ring to colorless products, a process supported by the enhancement by D2O and quenching by azide of RB photobleaching (Figure 6). In contrast, in a previous report, RB triplets were not detected in RB aggregates bound to collagen thus precluding a role for 1O2. (22)
Electron transfer from Arg to RB triplet may initiate collagen–collagen cross-linking because arginine enhanced the RB photodegradation rates of both aggregated and monomeric dye (Figures 5 and 6) and quenched the RB triplet (Figures S8 and 8). Early studies of photoreduction of monomeric RB by amines identified dehalogenation products, especially the 510 nm absorbing 2,7-diiodotetrachloro-fluorescein. (20) Our results show the appearance of this product clearly for aggregated RB in the presence of Arg under N2, considerably less formed in air, and practically none in oxygen-saturated solutions (Figure 5). Significantly, this result suggests that triplet quenching within the aggregates does not preclude reactions with external electron donors. Dehalogenation results from initial electron transfer from Arg to the dye triplet producing the RB anion radical and the amine cation radical. Subsequent deprotonation of the amine cation radical and rearrangement steps produce radical intermediates that could lead to protein–protein cross-linking. However, substantial yields of colorless products also form because the amount of dehalogenated product (based on the absorption coefficient for fluorescein) is much smaller than the amount of rose Bengal destroyed. These products may be the dihydro dye formed by initial electron transfer from ground state RB to RB triplet. (19, 32)
Rose Bengal photodegradation, when associated with native type 1 collagen in hydrogels (Figure 7), may mimic the photoreactions occurring in tissues during photo-cross-linking. The decrease in RB absorption was accompanied by a blue shift of the peak (Figure 7) indicating dehalogenation, which is similar to the result obtained for RB aggregates in the presence of Arg and ascorbate (Figures S7 and 5). If so, it would suggest that the electron-donating amino acids in native collagen are able to act as reaction partners of aggregated rose Bengal triplet excited state to initiate a radical pathway potentially involved in collagen cross-linking. Because Arg but not Lys increased RB photobleaching, the electron donor may be arginine. Side chains of both amino acids are positively charged and capable of participating in binding RB through ionic interactions, as shown for lysine in the CLP (Figures 3 and 4). In fact, in a recent study by part of our team, we used a polymeric form of lysine (poly-l-lysine), in the rose Bengal cross-linking of acrylate-modified collagen, which resulted in an enhancement of the composite elasticity along with preventing the dye photodegradation. (33) Those findings point toward possible intramolecular reactions between a rose Bengal reactive intermediate and the Lys residues, which resulted in the regeneration of the dye.
Arginine also effectively enhanced photobleaching of RB aggregates bound to collagen both in solution (Figure 6) and in collagen hydrogels (Figure 7). In hydrogels, triplet rose Bengal was readily quenched by Arg (Figure 8), and a further shift of the absorption spectrum toward the 510 nm deiodinated product was observed, see Figure 7. Thus, it appears that Arg reacts even more efficiently with triplet excited state rose Bengal in aggregates than the reducing amino acids in native collagen. If this observation is substantiated in tissues, it would suggest that Arg might be used to enhance the efficiency of rose Bengal photosensitized medical treatments, assuming that electron transfer processes initiate protein–protein cross-linking. Interestingly, rose Bengal triplet lifetime was not influenced by tryptophan when bound to the collagen matrix, which suggests limited diffusion/accessibility of the quencher within the 3D matrix (Figure 8b).
Oxygen may play different roles in photosensitized protein cross-linking depending on the tissue being treated and the treatment conditions. The normal O2 level in tissues decreases during photosensitization because O2 is removed by reactions of 1O2 with proteins and lipids. (34) Depending on the depth in tissue and the irradiance, O2 may not be replenished sufficiently rapidly by diffusion, and energy transfer from rose Bengal triplet to form 1O2 becomes inefficient. In this case, initial electron transfer to triplet state RB is favored and dehalogenation would be predicted as observed for the dye in collagen hydrogels (Figure 8). In the collagen hydrogels, 1O2 was observed but RB triplet lifetime was unchanged, suggesting that a process such as electron transfer dominates. Possibly, an initial electron transfer pathway for protein cross-linking could still show enhancement in O2 if intermediates trapped by O2 lead to cross-linking. Further studies to evaluate these possibilities are planned.

4 Summary and Conclusions

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Binding of rose Bengal to collagen is a complex process that includes competitive binding of dye monomer and aggregate to the protein chains. Molecular dynamics simulation of RB binding to a collagen-like peptide indicated that up to 16 ± 3 rose Bengal molecules can bind to an assembled peptide triple helix, with many bound as aggregates. Ionic interactions between negatively charged RB and protonated amino groups dominated contributions to the global free-energy minimum. In solution at low oxygen level, Rose Bengal photodegradation produced a 510 nm species, likely a dehalogenation product in the presence of arginine. Within a tissue-mimetic collagen matrix, irradiation yielded the 510 nm product suggesting that amino acids in the collagen chains are able to donate electrons to RB triplet and potentially initiate a protein cross-linking mechanism. Surprisingly, nonquenchable RB triplets and singlet oxygen were detected in the collagen matrix, suggesting an alternative oxidative mechanism for protein cross-linking in tissue. Although additional work is still needed, our work presents a comprehensive study on the role of rose Bengal–collagen interactions that may allow the design and engineering of novel dyes and materials for tissue photobonding.

5 Materials and Methods

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5.1 Materials

Rose Bengal (4,5,6,7-tetrachloro-2′,4′,5′,7′-tetra-iodofluorescein) sodium salt (≥99%), l-lysine, and l-ascorbic acid were obtained from Sigma-Aldrich. Type I medical grade porcine collagen (TheraCol) was purchased from Sewon Cellontech Co. Ltd. (Seoul, South Korea). Unless otherwise indicated, all solutions were prepared using Milli-Q water.

5.2 Effect of Collagen and Collagen-Like Peptides on Rose Bengal Spectroscopic Properties

The effect of macromolecule addition on the absorption spectrum of rose Bengal was studied in a manner similar to that previously described by part of our team. (22) All measurements in solution were carried out in 10 mM MES buffer (pH 5.0) in which collagen remains soluble and assembled. Rose Bengal solutions (20 μM) prepared in MES buffer were mixed in a 1:1 ratio with collagen solutions with concentrations up to 5.0 μM. The absorption spectra were measured in 1.0 cm cuvettes (Luzchem Inc.) using a Cary-100-Bio UV–visible spectrophotometer at room temperature (300–700 nm). Measurements were carried out using either native or thermally denatured collagen (95 °C for 5 min). Data shown correspond to the average from three independent experiments, each one carried out in quadruplicate. A similar protocol was used for the collagen-like peptide (CLP), where a higher concentration (up to 460 μM) was required to observe spectral changes similar to those observed for type I collagen.

5.3 Changes in Collagen Surface Charge

Changes in ζ potential for type I porcine collagen upon addition of the increasing concentrations of rose Bengal were carried out in a Malvern Zetasizer Nano ZS at 20 °C in 1.0 cm pathlength disposable ζ potential cuvettes. Reported values correspond to the average of three independent batches, each measured in triplicate.

5.4 Isothermal Titration Calorimetry (ITC)

ITC titrations were performed on a VP-ITC MicroCalorimeter from Malvern at 22 °C by using 10 μL injection with a total of up to 10 injections. Measurements were carried out in 10 mM MES buffer at pH 5.0. Data were processed using the Microcal Origin software. Two different sets of experiments were carried out using ITC. In the first set of experiments, increasing concentrations of CLP were added from a 10 mM concentrated solution up to 600 μM. In the second set of experiments, RB was added to a 450 μM CLP solution prepared in 10 mM, pH 5.0 MES buffer.

5.5 Collagen Matrix Preparation and Characterization

Briefly, type I medical grade porcine collagen was mixed with phosphate buffer saline pH 7.4, and cross-linked with 1.5% glutaraldehyde in ice. Unreacted aldehydes were deactivated with glycine. Rose Bengal was added to the mixture at a final concentration of 40 μM. The resulting viscous matrix, which cross-links in ≤30 min at 37 °C, has pore sizes in the range of 60 ± 10 μm as indicated by CRYO-SEM measurements for the collagen matrices.
The micromorphology of the collagen matrices was assessed using low temperature scanning electron microscopy (Cryo-SEM) in a Tescan (model: Vega II–XMU) equipped with a cold stage sample holder at −50 °C using a backscattered electron detector (BSE) and a secondary electron detector (SED). Pore sizes were measured from at least 400 individual pores using ImageJ software, similar to that described for other collagen matrices. (35)
Differential scanning calorimetry measurements were carried out for the hydrogels with and without the different concentrations of RB. Once chemically cross-linked, the hydrogels were thoroughly washed with PBS buffer pH 7.4 for 12 h prior to measuring their glass-transition temperature (Tg) in a Q2000 differential scanning calorimeter (TA Instruments). Heating scans were recorded within the range of 8–80°C at a scan rate of 10°C/min. Tg is defined as the onset of the endothermic peak.

5.6 Computer Simulations

5.6.1 Generation of Molecular Models

As a first step, the SWISS-model server (36) was used to generate the homology model of the collagen-like peptide (CLP) from the sequence CG(PKG)4(POG)4(DOG)4 (where O represents the amino acid hydroxyproline). On the basis of the sequence identity of 81.48% between collagen and this collagen-like peptide, we used an experimentally derived collagen structure (PDB ID: 1NAY) (27) as a template. As the percentage of coverage of the target sequence with respect to the template structure was 81%, the structure generated for the sequence DOG was replicated manually to build the final model of CLP. The homology model was generated in the multimeric triple helix structure based on the template. The model was solvated with the standard TIP3P water model of CHARMM in a periodic box of 52 × 52 × 154 Å3. Na+ and Cl– ions were added to neutralize the systems and obtain NaCl concentrations of 150 mM. The atomic interactions of RB were described by the CHARMM General Force Field (37) and parameters assigned by the ParamChem webserver (38, 39) based on RB in the −2 charge state (22) (with one carboxylate– and one phenolate–). All systems were assembled using VMD 1.9.2 software. (40)

5.6.2 Classical Molecular Dynamics Simulation

All simulations were performed in the molecular dynamics software NAMD 2.12 (41) and the all-atom CHARMM36 force field. (40, 42) Using the Langevin thermostat and Langevin piston method, (43) we maintained the temperature and pressure at 300 K and 101.325 kPa (1.0 atm), respectively. A smooth 8–9 Å cutoff of van der Waals forces was employed. The particle-mesh Ewald algorithm (44) was used to compute the electrostatic interactions with a mesh spacing of <1.2 Å. The length of covalent bonds involving hydrogen atoms was constrained (45, 46) to the values prescribed by the CHARMM force field. The masses of nonwater hydrogen atoms were increased by a factor of 3 (to 3.0240 Da) by transferring mass from the heavy atom to which they were attached, allowing us to integrate the equation of motion with a time step of 4 fs with no appreciable loss of accuracy in thermodynamic quantities. (47) All systems were relaxed for 25 000 steps of energy minimization followed by 20.0 ns of equilibration before beginning 250 ns of data production or free-energy calculations. For convenience, orientational restraints were applied to keep the long axis of the collagen-like peptide triple helix aligned along the Z axis using the Colvars module. (48) As these restraints were applied as a torque to the entire triple helix, they do not lead to any bias in the protein conformation nor in its interaction with RB. H-bonds were identified using the criteria of donor acceptor distances <3.5 Å and donor–H–acceptor angles > 120°.

5.6.3 Free-Energy Calculations

Beginning with the equilibrated systems, the adaptive biasing force (49-51) method was applied to calculate the free energy as a function of two transition coordinates: disZ, the position of RB along the Z axis with respect to the center of mass of the peptide, and disXY, the distance between the dye and the Z axis (passing through the center of mass of the peptide), that is, disXY = ρ = (X2 + Y2)1/2. This produced a two-dimensional potential of mean force as a function of position along the axis of the triple helix and in the plane orthogonal to this axis. The adaptive biasing force method was implemented through the Colvars module (48) of NAMD 2.12. (41) The first collective variable was sampled using a multiple window scheme, with a total of 7 windows on the interval −70 ≤ disZ ≥ 70 Å. The second collective variable was sampled in a single window on the interval 0 ≤ disXY ≥ 25 Å for each window in disZ. Each window was simulated for at least 340 ns, for a total of 2400 ns over all windows.
For systems with higher concentrations of RB, the free energy was estimated through straightforward equilibrium sampling, rather than by the adaptive biasing force method. Five systems containing the collagen-like peptide and 20 randomly placed RB molecules were created and simulated for 250 ns each with no biases. The free energy as a function of disZ and disXY was inferred from the average position distribution of RB molecules in the five systems during the last 200 ns of simulation (after 50 ns of equilibration). Because disXY is a cylindrical radial coordinate, it possesses a nonuniform geometric (Jacobian) contribution to the potential of mean force. The plots of the two-dimensional potentials of mean force in this work are shown with this geometric contribution removed, that is, the free energy far from the peptide axis is uniform rather than decreasing as −kBT ln ρ, due to the increasing amount of phase space for larger radii, 2πρ dρ.

5.7 Light-Mediated Degradation of Rose Bengal in Homogenous Solution and 3D Collagen Matrix

Sample solutions (570 μL) were irradiated in a plastic well (circular area = 1.9 cm2, pathlength = 3 mm) in a cylindrical chamber (height = 2 cm, inner diameter = 4.5 cm) with removable poly(methyl methacrylate) windows and gas inlet and exit ports on the sides. Laser light (532 nm; CW KTP frequency-doubled laser, Oculight OR, IRIDEX Corporation, Mountain View, CA) was delivered via an optical fiber through the upper window and centered on the sample well with an irradiance of approximately 0.3 W/cm2 at the sample surface.
The gas composition within the irradiation chamber was changed between N2, O2, and air (20% O2). Before an irradiation, the chamber was purged with N2 or O2, then the flow was stopped for 5 min to allow diffusion into the solution. This process was repeated three times. During the irradiation, a moderate flow of gas was allowed. For experiments in an air atmosphere, the top chamber window was removed, and the power of laser was lowered by 8.0% to compensate for the loss of light when the window is used.
Prior to irradiation and periodically during the irradiation, spectra of the samples were recorded without opening the irradiation chamber. A polychromatic halogen lamp was placed above the chamber and the transmitted light was collected with an integrating sphere (model FOIS, Ocean Optics) and analyzed with an Ocean Optics QEPro spectrometer. The laser light delivery fiber was moved from the irradiation position during each transmission measurement. Changes in transmission at the selected wavelength as a function of irradiation time were analyzed. Absorbance at 550 nm was used unless the absorbance of the initial spectrum of the 125 μM RB solution was higher than 2 when absorbance at 515 nm was also analyzed. The absorbance was calculated by taking the average of values of three adjacent data points to minimize the effect of noise in signals.
Irradiation of collagen solutions and hydrogels was carried out using a custom-made irradiation system equipped with a 523 ± 5 nm LED (LZ4-00G110 LED unit, LedEngin, Inc.) mounted on a PAR25 LED Cooler 32 W Synjet that dissipates the heating produced by the light source. The light source was collimated with an aluminum tube (ø 10 mm) into a 1.0 cm optical pathlength cuvette holder (CUV-UV, Ocean optics). Total light fluence was matched to the amount delivered in the experiments using the continuous wave laser detailed above, but using half of the light irradiance, ≈0.15 W/cm2.

5.8 Rose Bengal Laser Flash Photolysis

RB triplet transient absorption measurements were carried out in a LFP 111 laser flash photolysis system (Luzchem Inc., Ottawa, Canada) equipped with a Surlite OPO Plus (pump with a Nd-YAG 355 nm) operating at 550 nm and 10 mJ/pulse in 1.0 cm pathlength fused silica cuvettes (Luzchem Inc.). Triplet absorption of RB was measured at 620 nm under conditions of minimal dye bleaching (less than 5%). Two different sets of experiments were carried out using time-resolved techniques: (1) Effect of amino acids on the triplet lifetime of RB in solution: Measurements were carried out in 10 mM MES buffer pH 5.0 using a 10 μM dye concentration. Samples were degassed using 99.99% pure N2 for 1.0 h and increasing concentrations of l-arginine (Arg) and l-tryptophan (Trp) were added and the lifetime of RB triplet excited state was measured. Bimolecular rate constants were calculated from plotting kobs = k0 + kqx[Q], where kobs, k0, and kq correspond to the observed rate constant, rate constant in the absence of the quencher, and the bimolecular rate constant, respectively. (2) Effect of quenchers on RB reactive intermediates incorporated within collagen hydrogels: Collagen matrices were prepared as described above and the dye was incorporated within the 3D structure before solidification. The RB concentration was kept at 40 μM. Hydrogels were equilibrated for 3 h prior to measurements in solutions of the quenchers (Arg [5.0 mM], Trp [1.0 mM], and sodium azide (NaN3) [10 mM]) prepared in phosphate buffer with pH 7.4. Samples were degassed using 99.99% pure N2 for 2 h prior to measurements. In addition to the measurements for the triplet absorption at 620 nm, we monitored the bleaching of the ground state at 550 nm, and cation and anion radicals at 480 and 420 nm, respectively. Additional measurements for 1O2 emission upon excitation of the dye incorporated within the collagen matrix were also carried out. Singlet oxygen generation was quantified by following its phosphorescence decay at 1270 nm with a Hamamatsu NIR detector (peltier cooled at −62.8 °C operating at 800 V) after 550 nm laser excitation Surlite OPO Plus (pump with a Nd-YAG 355 nm), 10 mJ/pulse. Data were acquired and processed with customized Luzchem Research software. Measurements were carried out in deuterated PBS buffer pD 7.0.

5.9 Statistical Analyses

Student’s t-test (unpaired data with unequal variance) using a confidence interval of p < 0.05 was considered to identify statistically significant differences. Analyses were carried out in Kaleida Graph 4.5.

Supporting Information

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.7b00675.

  • Effect of type I porcine collagen, up to 2.5 μM, on the absorption spectra of 10 μM RB; representative circular dichroism spectra for a 1.25 μM rose Bengal solution with or without 5.0 μM type I collagen; isothermal titration calorimetry measurements for binding of rose Bengal to a collagen-like peptide (CLP); ζ potential measurements for 2.5 μM type I collagen in 10 mM pH 5.0 MES buffer in the presence of different rose Bengal concentrations; schematic representation for the preparation of RB containing collagen hydrogels; photodecomposition of rose Bengal (125 μM) under oxygen, air, and nitrogen saturated solutions; photodecomposition of RB (125 μM) in the presence of 1.25 mM sodium ascorbate in oxygen, air, and nitrogen saturated solutions; triplet transient lifetime and quenching of RB excited state in the presence of different quenchers; tryptophan degradation mediated by green light exposure in the RB containing collagen matrix (PDF)

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Author Information

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  • Corresponding Authors
    • Emilio I. Alarcon - Division of Cardiac Surgery, University of Ottawa Heart Institute, 40 Ruskin Street, K1Y 4W7 Ottawa, ON, Canada;  Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, K1H 8M5 Ottawa, ON, Canada;  Orcidhttp://orcid.org/0000-0001-5100-6179;  Email: [email protected]
    • Jeffrey Comer - Institute of Computational Comparative Medicine, Nanotechnology Innovation Center of Kansas State, and Department of Anatomy and Physiology, Kansas State University, Manhattan, Kansas 66503, United States;  Orcidhttp://orcid.org/0000-0003-4437-1260;  Email: [email protected]
  • Authors
    • Horacio Poblete - Center for Bioinformatics and Molecular Simulation, Universidad de Talca, 2 Norte 685, Casilla 721, Talca 3460000, Chile;  Institute of Computational Comparative Medicine, Nanotechnology Innovation Center of Kansas State, and Department of Anatomy and Physiology, Kansas State University, Manhattan, Kansas 66503, United States
    • HeeGwang Roh - Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, 40 Blossom Street, Boston, Massachusetts 02114, United States
    • Jean-François Couture - Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, K1H 8M5 Ottawa, ON, Canada
    • Irene E. Kochevar - Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, 40 Blossom Street, Boston, Massachusetts 02114, United States
  • Funding

    This work was made possible by funding from the Natural Sciences and Engineering Research Council (NSERC, RGPIN- 2015-0632) and from the Canadian Institutes of Health Research (CIHR) to E.I.A. E.I.A. also thanks UOHI start-up grant 1255. E.I.A. and I.E.K. thank the Burroughs Wellcome Fund for a Travel Grant. H.P. thanks Núcleo Científico Multidisciplinario de la Universidad de Talca, Chile, and grant no. 1171155 from Fondecyt, Chile. J.C. was partially supported by the Kansas Bioscience Authority funds to the Institute of Computational Comparative Medicine (ICCM) at Kansas State University and to the Nanotechnology Innovation Center of Kansas State University (NICKS). Computing for this project was performed on the Beocat Research Cluster at Kansas State University, which is funded in part by NSF grants CNS-1006860, EPS-1006860, and EPS-0919443. This work also used the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by National Science Foundation grant number ACI-1053575. H.G.R. was supported by the Harvard-MIT Summer Institute at MGH, National Science Foundation Grant EEC-1358296.

  • Notes
    The authors declare no competing financial interest.

Acknowledgment

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The authors would like to thank Professor Tito Scaiano for the time-resolved measurements. E.I.A. thanks Michel Grenier from University of Ottawa for his assistance with the laser flash photolysis experiments. The authors would like also to express their gratitude to Dr. May Griffith from University of Montreal for providing a sample of the CLP peptide. I.E.K. and H.G.R. would like to thank Dr. Walfre Franco and Antonio Ortega-Martinez for technical support.

Abbreviations

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Arg

l-arginine

CLP

collagen-like peptide

PTB

photochemical tissue bonding

RB

rose Bengal

Trp

l-tryptophan

References

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This article references 51 other publications.

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    Chan, B. P.; Amann, C.; Yaroslavsky, A. N.; Title, C.; Smink, D.; Zarins, B.; Kochevar, I. E.; Redmond, R. W. Photochemical repair of Achilles tendon rupture in a rat model J. Surg. Res. 2005, 124, 274– 279 DOI: 10.1016/j.jss.2004.09.019
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    Photochem. tissue bonding (PTB) is an emerging technique for bonding or sealing tissue surfaces that requires light and a photoactive dye for its effect. The potential of PTB for tendon repair was assessed in a rat model. The optical properties of bovine tendon were detd. ex vivo to gauge the depth of light penetration as a function of wavelength and dosimetry parameters were established for PTB repair of ruptured tendon. PTB was then tested in vivo to repair transected tendons in Sprague-Dawley rats. Repair strengths were measured using a strain gauge up to 14 days post treatment. The effective penetration depth in tendon was estd. to be 0.68 mm at 514 nm. Following PTB treatment of mech. ruptured tendon, significant bonding was dependent on the presence of both light and dye and attained a plateau strength at a fluence of 125 J/cm2. In a subsequent in vivo study to investigate PTB for repair of transected rat Achilles tendon, the ultimate stress required to break the repaired tendon was measured immediately after irradn. and at 7 and 14 days post-repair. Results showed that the difference in the ultimate stress between control and PTB treatment groups was statistically significant immediately after treatment and at 7 days (p = 0.04) but not 14 days (p = 0.75) post-repair. PTB provides a benefit to tendon repair at early stages in repair and is worthy of further investigation as a potential surgical adjunct for tendon repair in orthopedic surgeries.
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    Journal of reconstructive microsurgery (2016), 32 (6), 421-30 ISSN:.
    Introduction Photochemical tissue bonding (PTB) uses visible light to create sutureless, watertight bonds between two apposed tissue surfaces stained with photoactive dye. In phase 1 of this two-phase study, nerve gaps repaired with bonded isografts were superior to sutured isografts. When autograft demand exceeds supply, acellular nerve allograft (ANA) is an alternative although outcomes are typically inferior. This study assesses the efficacy of PTB when used with ANA. Methods Overall 20 male Lewis rats had 15-mm left sciatic nerve gaps repaired using ANA. ANAs were secured using epineurial suture (group 1) or PTB (group 2). Outcomes were assessed using sciatic function index (SFI), gastrocnemius muscle mass retention, and nerve histomorphometry. Historical controls from phase 1 were used to compare the performance of ANA with isograft. Statistical analysis was performed using analysis of variance and Bonferroni all-pairs comparison. Results All ANAs had signs of successful regeneration. Mean values for SFI, muscle mass retention, nerve fiber diameter, axon diameter, and myelin thickness were not significantly different between ANA + suture and ANA + PTB. On comparative analysis, ANA + suture performed significantly worse than isograft + suture from phase 1. However, ANA + PTB was statistically comparable to isograft + suture, the current standard of care. Conclusion Previously reported advantages of PTB versus suture appear to be reduced when applied to ANA. The lack of Schwann cells and neurotrophic factors may be responsible. PTB may improve ANA performance to an extent, where they are equivalent to autograft. This may have important clinical implications when injuries preclude the use of autograft.
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    Mulroy, L.; Kim, J.; Wu, I.; Scharper, P.; Melki, S. A.; Azar, D. T.; Redmond, R. W.; Kochevar, I. E. Photochemical keratodesmos for repair of lamellar corneal incisions Invest. Ophthalmol. Visual Sci. 2000, 41, 3335– 3340
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    O'Neill Anne C; Winograd Jonathan M; Zeballos Jose L; Johnson T Shane; Randolph Mark A; Bujold Kenneth E; Kochevar Irene E; Redmond Robert W
    Lasers in surgery and medicine (2007), 39 (9), 716-22 ISSN:0196-8092.
    BACKGROUND AND OBJECTIVES: Photochemical tissue bonding (PTB) combines photoactive dyes with visible light to create fluid-tight seals between tissue surfaces without causing collateral thermal damage. The potential of PTB to improve outcomes over standard of care microsurgical reanastomoses of blood vessels in ex vivo and in vivo models was evaluated. STUDY DESIGN: The mechanical strength and integrity of PTB and standard microsurgical suture repairs in ex vivo porcine brachial arteries (n = 10) were compared using hydrostatic testing of leak point pressure (LPP). Femoral artery repair in vivo was measured in Sprague-Dawley rats using either standard microvascular sutures (n = 20) or PTB (n = 20). Patency was evaluated at 6 hours (n = 10) and 8 weeks post-repair (n = 10) for each group. RESULTS: PTB produced significantly higher LPPs (1,100+/- 150 mmHg) than suture repair (350+/-40 mmHg, P<0.001) in an ex vivo study. In an in vivo study all femoral arteries in both suture and PTB repair groups were patent at 6 hours post-repair. At 8 weeks post-repair the patency rate was 80% for both groups. No evidence of aneurysm formation was seen in either group and bleeding was absent from the repair site in the PTB-treated vessels, in contrast to the suture repair group. CONCLUSION: PTB is a feasible microvascular repair technique that results in an immediate, mechanically robust bond with short- and long-term patency rates equal to those for standard suture repair.
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  5. 5
    Senthil-Kumar, P.; Ni, T.; Randolph, M. A.; Velmahos, G. C.; Kochevar, I. E.; Redmond, R. W. A light-activated amnion wrap strengthens colonic anastomosis and reduces peri-anastomotic adhesions Lasers Surg. Med. 2016, 48, 530– 537 DOI: 10.1002/lsm.22507
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    5
    A light-activated amnion wrap strengthens colonic anastomosis and reduces peri-anastomotic adhesions
    Senthil-Kumar Prabhu; Ni Tao; Kochevar Irene E; Redmond Robert W; Senthil-Kumar Prabhu; Randolph Mark A; Ni Tao; Velmahos George C
    Lasers in surgery and medicine (2016), 48 (5), 530-7 ISSN:.
    BACKGROUND AND OBJECTIVE: Colonic anastomotic failure is a dreaded complication, and multiple surgical techniques have failed to eliminate it. Photochemical tissue bonding (PTB) is a method of sealing tissue surfaces by light-activated crosslinking. We evaluated if a human amniotic membrane (HAM), sealed over the anastomotic line by PTB, increases the anastomotic strength. STUDY DESIGN: Sprague-Dawley rats underwent midline laparotomy followed by surgical transection of the left colon. Animals were randomized to colonic anastomosis by one of the following methods (20 per group): single-layer continuous circumferential suture repair (SR); SR with a HAM wrap attached by suture (SR+ HAM-S); SR with HAM bonded photochemically over the anastomotic site using 532 nm light (SR+ HAM-PTB); approximation of the bowel ends with only three sutures and sealing with HAM-PTB (3+ HAM-PTB). A control group underwent laparotomy alone with no colon resection (NR). Sub-groups (n = 10) were sacrificed at days 3 and 7 post-operatively and adhesions were evaluated. A 6 cm section of colon was then removed and strength of anastomosis evaluated by burst pressure (BP) measurement. RESULTS: A fourfold increase in BP was observed in the SR+ HAM-PTB group compared to suture repair alone (94 ± 3 vs. 25 ± 8 mm Hg, P < 0.0001) at day 3. At day 7 the burst pressures were 165 ± 40 and 145 ± 31 mm Hg (P = 1), respectively. A significant decrease in peri-anastomotic adhesions was observed in the SR+ HAM-PTB group compared to the SR group at both time points (P < 0.001). CONCLUSION: Sealing sutured colonic anastomotic lines with HAM-PTB increases the early strength of the repair and reduces peri-anastomotic adhesions. Lasers Surg. Med. 48:530-537, 2016. © 2016 Wiley Periodicals, Inc.
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  6. 6
    Tsao, S.; Yao, M.; Tsao, H.; Henry, F. P.; Zhao, Y.; Kochevar, J. J.; Redmond, R. W.; Kochevar, I. E. Light-activated tissue bonding for excisional wound closure: a split-lesion clinical trial Br. J. Dermatol. 2012, 166, 555– 563 DOI: 10.1111/j.1365-2133.2011.10710.x
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    6
    Light-activated tissue bonding for excisional wound closure: a split-lesion clinical trial
    Tsao S; Yao M; Tsao H; Henry F P; Zhao Y; Kochevar J J; Redmond R W; Kochevar I E
    The British journal of dermatology (2012), 166 (3), 555-63 ISSN:.
    BACKGROUND: Apposition of wound edges by sutures provides a temporary scaffold and tension support for healing. We have developed a novel tissue-sealing technology, photoactivated tissue bonding (PTB), which immediately crosslinks proteins between tissue planes, thereby sealing on a molecular scale. OBJECTIVES: To determine the effectiveness of PTB for superficial closure of skin excisions and to compare the results with standard epidermal suturing. METHODS: A split-lesion, paired comparison study of 31 skin excisions was performed. Following deep closure with absorbable sutures, one-half of each wound was superficially closed with nonabsorbable nylon sutures while the other half was stained with Rose Bengal dye and treated with green light. Overall appearance and scar characteristics were rated at 2weeks and 6months in a blinded manner by three dermatologists viewing photographs, by two onsite physicians and by patients. RESULTS: At 2weeks, neither sutured nor PTB-treated segments showed dehiscence; however, PTB-sealed segments showed less erythema than sutured segments as determined by photographic (P=0·001) and onsite evaluations (P=0·005). Overall appearance after PTB was judged better than after sutures (P=0·002). At 6months, scars produced by PTB were deemed superior to scars resulting from sutures in terms of appearance (P<0·001), width (P=0·002) and healing (P=0·003). Patients were more satisfied with the appearance of the PTB-sealed wound half after 2weeks and 6months (P=0·013 and P=0·003, respectively). CONCLUSIONS: A novel molecular suturing technique produces effective wound sealing and less scarring than closure with nylon interrupted epidermal sutures. Comparisons with better suturing techniques are warranted.
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  7. 7
    Verter, E. E.; Gisel, T. E.; Yang, P.; Johnson, A. J.; Redmond, R. W.; Kochevar, I. E. Light-initiated bonding of amniotic membrane to cornea Invest. Ophthalmol. Visual Sci. 2011, 52, 9470– 9477 DOI: 10.1167/iovs.11-7248
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    7
    Light-initiated bonding of amniotic membrane to cornea
    Verter, E. Eri; Gisel, Thomas E.; Yang, Penggao; Johnson, Anthony J.; Redmond, Robert W.; Kochevar, Irene E.
    Investigative Ophthalmology & Visual Science (2011), 52 (13), 9470-9477CODEN: IOVSDA; ISSN:1552-5783. (Association for Research in Vision and Ophthalmology)
    Purpose: Suturing amniotic membrane to cornea during surgery is time consuming, and sutures may further damage the eye. The authors introduce a novel sutureless, light-activated technique that securely attaches amnion to cornea through protein-protein crosslinks. Methods: Cryopreserved human amniotic membrane, stained with Rose Bengal (RB), was placed over a full-thickness wound in deepithelialized rabbit cornea and was treated with green laser. The intraocular pressure that broke the seal (IOPL) was measured, and adhesion was measured with a peel test. The influences on bonding strength of fluence, irradiance, RB concn., and amnion surface bonded were measured. Epithelial cell migration on treated amnion and keratocyte viability after bonding were also measured. The involvement in the bonding mechanism of oxygen, singlet oxygen, and assocn. of RB with stromal collagen was investigated. Results: Sealing amniotic membrane over cornea using 0.1% RB and 150 J/cm2 at 532 nm produced an IOPL of 261 ± 77 mm Hg ex vivo and 448 mm ± 212 mm Hg in vivo. The ex vivo IOPL increased with increasing fluence (50-150 J/cm2). Equivalent IOPL was produced for bonding basement membrane or stromal amnion surfaces. The bonding treatment was not toxic to keratocytes but slightly reduced the migration of corneal epithelial cells on amnion ex vivo. Mechanism studies indicated that RB forms two complexes with amnion stromal collagen, that bonding requires oxygen, and that singlet oxygen mediates protein crosslinking. Conclusions: A rapid, light-activated technique produces strong, immediate bonding between amnion and cornea and merits further evaluation for ocular surface surgeries.
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  8. 8
    Cherfan, D.; Verter, E. E.; Melki, S.; Gisel, T. E.; Doyle, F. J., Jr.; Scarcelli, G.; Yun, S. H.; Redmond, R. W.; Kochevar, I. E. Collagen cross-linking using rose bengal and green light to increase corneal stiffness Invest. Ophthalmol. Visual Sci. 2013, 54, 3426– 3433 DOI: 10.1167/iovs.12-11509
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    There is no corresponding record for this reference.
  9. 9
    Zhu, H.; Alt, C.; Webb, R. H.; Melki, S.; Kochevar, I. E. Corneal Crosslinking With Rose Bengal and Green Light: Efficacy and Safety Evaluation Cornea 2016, 35, 1234– 1241 DOI: 10.1097/ICO.0000000000000916
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    There is no corresponding record for this reference.
  10. 10
    Goldstone, R. N.; McCormack, M. C.; Goldstein, R. L.; Mallidi, S.; Randolph, M. A.; Watkins, M. T.; Redmond, R. W.; Austen, W. G., Jr. Photochemical Tissue Passivation Attenuates AV Fistula Intimal HyperplasiaAnn. Surg. 2016,  DOI: 10.1097/SLA.0000000000002046 .
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    There is no corresponding record for this reference.
  11. 11
    Goldstone, R. N.; McCormack, M. C.; Khan, S. I.; Salinas, H. M.; Meppelink, A.; Randolph, M. A.; Watkins, M. T.; Redmond, R. W.; Austen, W. G., Jr. Photochemical Tissue Passivation Reduces Vein Graft Intimal Hyperplasia in a Swine Model of Arteriovenous Bypass Grafting J. Am. Heart Assoc. 2016, 5e003856 DOI: 10.1161/JAHA.116.003856
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    11
    Photochemical tissue passivation reduces vein graft intimal hyperplasia in a swine model of arteriovenous bypass grafting
    Goldstone, Robert N.; McCormack, Michael C.; Khan, Saiqa I.; Salinas, Harry M.; Meppelink, Amanda; Randolph, Mark A.; Watkins, Michael T.; Redmond, Robert W.; Austen, William G. Jr.
    Journal of the American Heart Association (2016), 5 (8), e003856/1-e003856/10CODEN: JAHABZ; ISSN:2047-9980. (Wiley-Blackwell)
    Background-Bypass grafting remains the std. of care for coronary artery disease and severe lower extremity ischemia. Efficacy is limited by poor long-term venous graft patency secondary to intimal hyperplasia (IH) caused by venous injury upon exposure to arterial pressure. We investigate whether photochem. tissue passivation (PTP) treatment of vein grafts modulates smooth muscle cell (SMC) proliferation and migration, and inhibits development of IH. Methods and Results-PTP was performed at increasing fluences up to 120 J/cm2 on porcine veins. Tensiometry performed to assess vessel elasticity/stiffness showed increased stiffness with increasing fluence until plateauing at 90 J/cm2 (median, interquartile range [IQR]). At 90 J/cm2, PTP-treated vessels had a 10-fold greater Young's modulus than untreated controls (954 [IQR, 2217] vs 99 kPa [IQR, 63]; P=0.03). Each pig received a PTP-treated and untreated carotid artery venous interposition graft. At 4-wk, intimal/medial areas were assessed. PTP reduced the degree of IH by 66% and medial hypertrophy by 49%. Intimal area was 3.91 (IQR, 1.2) and 1.3 mm2 (IQR, 0.97; P≤0.001) in untreated and PTP-treated grafts, resp. Medial area was 9.2 (IQR, 3.2) and 4.7 mm2 (IQR, 2.0; P≤0.001) in untreated and PTP-treated grafts, resp. Immunohistochem. was performed to assess alpha-smooth muscle actin (SMA) and proliferating cell nuclear antigen (PCNA). Objectively, there were less SMA-pos. cells within the intima/media of PTP-treated vessels than controls. There was an increase in PCNA-pos. cells within control vein grafts (18% [IQR, 5.3]) vs. PTP-treated vein grafts (5% [IQR, 0.9]; P=0.02). Conclusions-By strengthening vein grafts, PTP decreases SMC proliferation and migration, thereby reducing IH.
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  12. 12
    Fernandes, J. R.; Salinas, H. M.; Broelsch, G. F.; McCormack, M. C.; Meppelink, A. M.; Randolph, M. A.; Redmond, R. W.; Austen, W. G., Jr. Prevention of capsular contracture with photochemical tissue passivation Plast. Reconstr. Surg. 2014, 133, 571– 577 DOI: 10.1097/01.prs.0000438063.31043.79
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    12
    Prevention of Capsular Contracture with Photochemical Tissue Passivation
    Fernandes, Justin R.; Salinas, Harry M.; Broelsch, G. Felix; McCormack, Michael C.; Meppelink, Amanda M.; Randolph, Mark A.; Redmond, Robert W.; Austen, William G., Jr.
    Plastic and Reconstructive Surgery (2014), 133 (3), 571-577CODEN: PRSUAS; ISSN:1529-4242. (Lippincott Williams & Wilkins)
    Background: Capsular contracture is the most common complication following the insertion of breast implants. Within a decade, half of patients will develop capsular contracture, leading to significant morbidity and need for reoperation. There is no preventative treatment available and the recurrence rate remains high. Photochem. tissue passivation is a novel tissue-stabilization technique that results in collagen crosslinking. It can rapidly link collagen fibers in situ, preserving normal tissue architecture. By using this therapy to passivate the collagenous tissues of the implant pocket, the authors hope to prevent the development of pathogenic collagen bundles and subsequent capsule contracture. Methods: Six-cubic centimeter tissue expanders were placed below the panniculus carnosus muscle along the dorsum of New Zealand white rabbits. Fibrin glue was instilled into each implant pocket to induce contracture. Treated pockets received photochem. tissue passivation by coating them with a photosensitizing dye and exposing the area to a 532-nm light. After 8 wk, capsule tissue was harvested for histol. evaluation. Results: Implant capsule thickness is the no. one prognostic factor for contracture development. The authors demonstrated a 52 percent decrease in capsule thickness in the passivated group compared with controls. Photochem. tissue passivation resulted in fewer fibrohistiocytic cells and macrophages and in reduced synovial metaplasia and smooth muscle actin deposition. Conclusions: Photochem. tissue passivation significantly decreased both capsule thickness and smooth muscle actin deposition. It is a promising technique for preventing capsular contracture that can be performed at the time of initial surgery without a significant increase in procedure time.
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  13. 13
    Ludvikova, L.; Fris, P.; Heger, D.; Sebej, P.; Wirz, J.; Klan, P. Photochemistry of rose bengal in water and acetonitrile: a comprehensive kinetic analysis Phys. Chem. Chem. Phys. 2016, 18, 16266– 16273 DOI: 10.1039/C6CP01710J
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    13
    Photochemistry of rose bengal in water and acetonitrile: a comprehensive kinetic analysis
    Ludvikova, Lucie; Fris, Pavel; Heger, Dominik; Sebej, Peter; Wirz, Jakob; Klan, Petr
    Physical Chemistry Chemical Physics (2016), 18 (24), 16266-16273CODEN: PPCPFQ; ISSN:1463-9076. (Royal Society of Chemistry)
    The photophys. and photochem. properties of rose bengal (RB) in degassed aq. and acetonitrile solns. were studied using steady-state and transient absorption spectroscopies. This comprehensive investigation provides detailed information about the kinetics and the optical properties of all intermediates involved: the triplet excited state and the oxidized and reduced forms of RB. A full kinetic description is used to control the concns. of these intermediates by changing the initial exptl. conditions.
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    Neckers, D. C. Rose Bengal J. Photochem. Photobiol. A 1989, 47, 1– 29 DOI: 10.1016/1010-6030(89)85002-6
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    Rose Bengal
    Neckers, D. C.
    Journal of Photochemistry and Photobiology, A: Chemistry (1989), 47 (1), 1-29CODEN: JPPCEJ; ISSN:1010-6030.
    A review with 38 refs. The spectral properties, photochem. reactivity, and photophys. parameters of all of the known derivs. of Rose Bengal, 2,4,5,7-tetraiodo-3',4',5',6'-tetrachlorofluorescein, are reported and compared.
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  15. 15
    Fleming, G. R.; Morris, J. M.; Morrison, R. J. S.; Robinson, G. W. Picosecond fluorescence studies of xanthene dyes J. Am. Chem. Soc. 1977, 99, 4306– 4311 DOI: 10.1021/ja00455a017
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    Picosecond fluorescence studies of xanthene dyes
    Fleming, G. R.; Knight, A. W. E.; Morris, J. M.; Morrison, R. J. S.; Robinson, G. W.
    Journal of the American Chemical Society (1977), 99 (13), 4306-11CODEN: JACSAT; ISSN:0002-7863.
    Subnanosecond lifetime measurements using picosecond pulses from a mode-locked Nd3+-glass laser together with conventional absorption and fluorescence-yield methods are used to study the photophys. of fluorescein, eosin, erythrosin, and rose bengal in aq. and alc. solvents. For each of the dye mols., absorption and fluorescence max. move towards higher energy (blue shift) as the solvent changes from Me2CHOH to H2O. Fluorescence lifetimes and quantum yields decrease with this solvent change and also with increased halogenation of the fluorescein parent, owing to the heavy-atom effect. The variations obsd. in the nonradiative part of the decay rate are attributed to variations in the rate of S1-T1 intersystem crossing. For these particular solvent-solute combinations stabilization energies lie in the order ΔE(T1) < ΔE(S1) < ΔE(S0). This is consistent with both the increased S1-S0 spectral blue shifts and the enhanced intersystem crossing rate, arising from a smaller S1-T1 energy gap, when these dye mols. are placed in a more aq. solvent environment. The use of these dyes as fluorescent probes in biol. important mols. is discussed.
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    Kochevar, I. E.; Redmond, R. W. Photosensitized production of singlet oxygen Methods Enzymol. 2000, 319, 20– 28 DOI: 10.1016/s0076-6879(00)19004-4
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    Photosensitized production of singlet oxygen
    Kochevar, Irene E.; Redmond, Robert W.
    Methods in Enzymology (2000), 319 (), 20-28CODEN: MENZAU; ISSN:0076-6879. (Academic Press)
    A review with 8 refs. Photosensitization is a simple and controllable method for the generation of singlet oxygen in soln. and in cells. Methods are described for detg. the yield of singlet oxygen in soln., for measurement of the rate of reaction between single oxygen and a substrate, and for comparing the effectiveness of singlet oxygen generated by different photosensitizers in cells. These quant. measurements can lead to better understanding of the interaction of singlet oxygen with biomols. (c) 2000 Academic Press.
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    Shen, H. R.; Spikes, J. D.; Kopeckova, P.; Kopecek, J. Photodynamic crosslinking of proteins. II. Photocrosslinking of a model protein-ribonuclease A J. Photochem. Photobiol. B 1996, 35, 213– 219 DOI: 10.1016/S1011-1344(96)07300-9
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    Photodynamic crosslinking of proteins. II. Photocrosslinking of a model protein-ribonuclease A
    Shen, Hui-Rong; Spikes, John D.; Kopeckova, Pavla; Kopecek, Jindrich
    Journal of Photochemistry and Photobiology, B: Biology (1996), 35 (3), 213-219CODEN: JPPBEG; ISSN:1011-1344. (Elsevier)
    Illumination of bovine pancreatic RNase A (RNase A) in soln. in the presence of rose bengal as a photosensitizer resulted in the progressive formation of enzyme dimers, trimers, tetramers and higher oligomers, as measured by gel electrophoresis and size exclusion chromatog. Oxygen was necessary for crosslink formation, and azide inhibition studies indicated that singlet oxygen was involved in the process. Chem. modification of His residues (with di-Et pyrocarbonate) and/or Lys residues (with acetic acid N-hydroxysuccinimide ester) in the enzyme decreased crosslinking, suggesting the participation of these two amino acid residues in the reaction. Met and cystine residues did not appear to be involved. Similar studies have shown that model N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers contg. ε-aminocaproic acid side chains terminating in His or Lys residues are photodynamically crosslinked via His-His or His-Lys interactions. Treatment of crosslinked RNase A and its His, Lys and Lys-His derivs. for 5 min at 97 °C in a dithiothreitol-sodium dodecyl sulfate mixt. efficiently ruptured a major part of the photodynamically formed crosslinks; treatment with the detergent alone had no effect. Similar results were previously obtained with the crosslinked amino acid-contg. HPMA copolymers, suggesting that photodynamic crosslinks involving His-His and His-Lys interaction are chem. the same in RNase A and the copolymer model.
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    Lambert, C. R.; Kochevar, I. E. Electron transfer quenching of the rose bengal triplet state Photochem. Photobiol. 1997, 66, 15– 25 DOI: 10.1111/j.1751-1097.1997.tb03133.x
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    Electron transfer quenching of the rose bengal triplet state
    Lambert, Christopher R.; Kochevar, Irene E.
    Photochemistry and Photobiology (1997), 66 (1), 15-25CODEN: PHCBAP; ISSN:0031-8655. (American Society for Photobiology)
    The potential for electron transfer quenching of rose bengal triplet (3RB2-) to compete with energy transfer quenching by oxygen was evaluated. Rate consts. for oxidative and reductive quenching were measured in buffered aq. soln., acetonitrile and in small unilamellar liposomes using laser flash photolysis. Biol. relevant quenchers were used that varied widely in structure, redn. potential and charge. Radical ion yields (φi) were measured by monitoring the absorption of the rose bengal semireduced (RB·3-) and semioxidized (RB·-) radicals. The results in soln. were analyzed as a function of the free energy for electron transfer (ΔG) calcd. using the Weller equation including electrostatic terms. Exothermic oxidative quenching was about 10-fold faster than exothermic reductive quenching in aq. soln. The quenching rate consts. decreased as ΔG approached zero in both aq. and acetonitrile soln. Exceptions to these generalizations were obsd. that could be rationalized by specific steric or electrostatic effects or by a change in mechanism. The results suggest that electron transfer reactions with some potential quenchers in cells could compete with formation of singlet oxygen [O2(1Δg)]. Values of φi were generally greater for reductive quenching and, for oxidative quenching, greater in acetonitrile than in buffer. Electron transfer quenching of 3RB2- in liposomes, below the phase transition temp. was slower than in soln. for both lipid-sol. and water-sol. quenchers indicating that these reactions may not compete with formation of (O21Δg) during cell photosensitization.
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    Zakrzewski, A.; Neckers, D. C. Bleaching products of rose bengal under reducing conditions Tetrahedron 1987, 43, 4507– 4512 DOI: 10.1016/S0040-4020(01)86891-5
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    Bleaching products of Rose Bengal under reducing conditions
    Zakrzewski, Andrzej; Neckers, D. C.
    Tetrahedron (1987), 43 (20), 4507-12CODEN: TETRAB; ISSN:0040-4020.
    The bleaching behavior of Rose Bengal under reducing conditions was elucidated by detg. the products of chem. and photochem. redn. of Rose Bengal.
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    Oster, G.; Oster, G. K.; Karg, G. Extremely long-lived intermediates in photochemical reactions of dyes in non-visous media J. Phys. Chem. 1962, 66, 2514– 2517 DOI: 10.1021/j100818a045
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    Luttrull, D. K.; Valdes-Aguilera, O.; Linden, S. M.; Paczkowski, J.; Neckers, D. C. Rose Bengal aggregation in rationally synthesized dimeric systems Photochem. Photobiol. 1988, 47, 551– 557 DOI: 10.1111/j.1751-1097.1988.tb08843.x
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    Simpson, M. J.; Poblete, H.; Griffith, M.; Alarcon, E. I.; Scaiano, J. C. Impact of dye-protein interaction and silver nanoparticles on rose bengal photophysical behavior and protein photocrosslinking Photochem. Photobiol. 2013, 89, 1433– 1441 DOI: 10.1111/php.12119
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    Valdes-Aguilera, O.; Neckers, D. C. Aggregation phenomena in xanthene dyes Acc. Chem. Res. 1989, 22, 171– 177 DOI: 10.1021/ar00161a002
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    Aggregation phenomena in xanthene dyes
    Valdes-Aguilera, Oscar; Neckers, D. C.
    Accounts of Chemical Research (1989), 22 (5), 171-7CODEN: ACHRE4; ISSN:0001-4842.
    A crit. review with 63 refs. on aggregation of xanthene dyes, principally rhodamines and fluoresceins. The author's work on Rose Bengal is considered in detail.
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    Xu, D.; Neckers, D. C. Aggregation of rose bengal molecules in solution J. Photochem. Photobiol. A 1987, 40, 361– 370 DOI: 10.1016/1010-6030(87)85013-X
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    Aggregation of Rose Bengal molecules in solution
    Xu, Danian; Neckers, D. C.
    Journal of Photochemistry and Photobiology, A: Chemistry (1987), 40 (2-3), 361-70CODEN: JPPCEJ; ISSN:1010-6030.
    Absorption, emission, and excitation spectral data support the hypothesis that Rose Bengal forms H-type aggregates in water and in polar, protic solvents.
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    Alarcón, E.; Edwards, A. M.; Aspee, A.; Borsarelli, C. D.; Lissi, E. A. Photophysics and photochemistry of rose bengal bound to human serum albumin Photochem. Photobiol. Sci. 2009, 8, 933– 943 DOI: 10.1039/b901056d
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    25
    Photophysics and photochemistry of rose bengal bound to human serum albumin
    Alarcon, Emilio; Edwards, Ana Maria; Aspee, Alexis; Borsarelli, Claudio D.; Lissi, Eduardo A.
    Photochemical & Photobiological Sciences (2009), 8 (7), 933-943CODEN: PPSHCB; ISSN:1474-905X. (Royal Society of Chemistry)
    Rose bengal (RB) readily binds to human serum albumin (HSA). At low RB concns., 90% of the dye is assocd. to the protein (5 μM). This assocn. takes place in specific binding sites I and/or II. At higher RB concns., unspecific binding takes place with up to 10 RB mols. bound per protein mol. The behavior of excited RB mols. bound to HSA is widely different to that obsd. in aq. soln. Furthermore, the data also show that the behavior of bound RB mols. changes with the av. no. of dye mols. per protein (n). In particular, when n is large, the fluorescence yield is significantly reduced and no measurable long-lived triples and free singlet oxygen formation from bound dyes is detected. These results are related to self-quenching of the singlet and, most likely, excited triplets. All results point to the relevance of intra-protein generated singlet oxygen. However, when the dye is bound to the protein, at low oxygen concns. such as those prevailing in vivo, trapping by oxygen of the triplet becomes inefficient and type I processes could contribute to the obsd. photoprocesses.
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    Ni, T.; Senthil-Kumar, P.; Dubbin, K.; Aznar-Cervantes, S. D.; Datta, N.; Randolph, M. A.; Cenis, J. L.; Rutledge, G. C.; Kochevar, I. E.; Redmond, R. W. A photoactivated nanofiber graft material for augmented Achilles tendon repair Lasers Surg. Med. 2012, 44, 645– 652 DOI: 10.1002/lsm.22066
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    A photoactivated nanofiber graft material for augmented Achilles tendon repair
    Ni Tao; Senthil-Kumar Prabhu; Dubbin Karen; Aznar-Cervantes Salvador D; Datta Neha; Randolph Mark A; Cenis Jose L; Rutledge Gregory C; Kochevar Irene E; Redmond Robert W
    Lasers in surgery and medicine (2012), 44 (8), 645-52 ISSN:.
    BACKGROUND AND OBJECTIVE: Suture repair of Achilles tendon rupture can cause infection, inflammation and scarring, while prolonged immobilization promotes adhesions to surrounding tissues and joint stiffness. Early mobilization can reduce complications provided the repair is strong enough to resist re-rupture. We have developed a biocompatible, photoactivated tendon wrap from electrospun silk (ES) to provide additional strength to the repair that could permit early mobilization, and act as a barrier to adhesion formation. STUDY DESIGN/MATERIAL AND METHODS: ES nanofiber mats were prepared by electrospinning. New Zealand white rabbits underwent surgical transection of the Achilles tendon and repair by: (a) SR: standard Kessler suture + epitendinous suture (5-0 vicryl). (b) ES/PTB: a single stay suture and a section of ES mat, stained with 0.1% Rose Bengal (RB), wrapped around the tendon and bonded with 532 nm light (0.3 W/cm(2) , 125 J/cm(2) ). (c) SR + ES/PTB: a combination of (a) and (b). Gross appearance, extent of adhesion formation and biomechanical properties of the repaired tendon were evaluated at Days 7, 14, or 28 post-operatively (n = 8 per group at each time point). RESULTS: Ultimate stress (US) and Young's modulus (E) in the SR group were not significantly different from the ES/PTB group at Days 7 (US, P = 0.85; E, P = 1), 14 (US, P = 0.054; E, P = 1), and 28 (US, P = 0.198; E, P = 0.12) post-operatively. Adhesions were considerably greater in the SR group compared to the ES/PTB group at Days 7 (P = 0.002), 14 (P < 0.0001), and 28 (P < 0.0001). The combination approach of SR + ES/PTB gave the best outcomes in terms of E at 7 (P < 0.016) and 14 days (P < 0.016) and reduced adhesions compared to SR at 7 (P < 0.0001) and 14 days (P < 0.0001), the latter suggesting a barrier function for the photobonded ES wrap. CONCLUSION: Photochemical sealing of a ES mat around the tendon repair site provides considerable benefit in Achilles tendon repair. Lasers Surg. Med. 44: 645-652, 2012. © 2012 Wiley Periodicals, Inc.
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    Stetefeld, J.; Frank, S.; Jenny, M.; Schulthess, T.; Kammerer, R. A.; Boudko, S.; Landwehr, R.; Okuyama, K.; Engel, J. Collagen stabilization at atomic level: crystal structure of designed (GlyProPro)10foldon Structure 2003, 11, 339– 346 DOI: 10.1016/S0969-2126(03)00025-X
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    Collagen Stabilization at Atomic Level Crystal Structure of Designed (GlyProPro)10foldon
    Stetefeld, Jorg; Frank, Sabine; Jenny, Margrit; Schulthess, Therese; Kammerer, Richard A.; Boudko, Sergei; Landwehr, Ruth; Okuyama, Kenji; Engel, Jurgen
    Structure (Cambridge, MA, United States) (2003), 11 (3), 339-346CODEN: STRUE6; ISSN:0969-2126. (Cell Press)
    In a designed fusion protein the trimeric domain foldon from bacteriophage T4 fibritin was connected to the C terminus of the collagen model peptide (GlyProPro)10 by a short Gly-Ser linker to facilitate formation of the three-stranded collagen triple helix. Crystal structure anal. at 2.6 A resoln. revealed conformational changes within the interface of both domains compared with the structure of the isolated mols. A striking feature is an angle of 62.5° between the symmetry axis of the foldon trimer and the axis of the triple helix. The melting temp. of (GlyProPro)10 in the designed fusion protein (GlyProPro)10foldon is higher than that of isolated (GlyProPro)10, which suggests an entropic stabilization compensating for the destabilization at the interface.
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    Mirenda, M.; Dicelio, L. E.; San Roman, E. Effect of molecular interactions on the photophysics of Rose Bengal in polyelectrolyte solutions and self-assembled thin films J. Phys. Chem. B 2008, 112, 12201– 12207 DOI: 10.1021/jp803892g
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    Effect of molecular interactions on the photophysics of Rose Bengal in polyelectrolyte solutions and self-assembled thin films
    Mirenda, Martin; Dicelio, Lelia E.; San Roman, Enrique
    Journal of Physical Chemistry B (2008), 112 (39), 12201-12207CODEN: JPCBFK; ISSN:1520-6106. (American Chemical Society)
    Aq. solns. and layer-by-layer self-assembled thin films contg. Rose Bengal and poly(diallyldimethylammonium chloride) are studied with the aim of understanding the interactions controlling their structures and the photophysics of the dye in both media. A detailed spectroscopic and theor. anal. shows that hydrophobic interactions among dye mols. contribute to the coiling of the polyelectrolyte chain in soln. at low polyelectrolyte/dye (P/D) ratios, whereas extensive aggregation of the dye takes place even at ratios as high as 104 (expressed in monomeric units). A polyelectrolyte elongated form prevails in self-assembled thin films, providing an environment that reduces hydrophobic interactions and lowers the aggregation tendency. Self-assembled films with a roughly estd. overall dye concn. around 1 M at a P/D ratio in the order of seven are fluorescent and photogenerate singlet mol. oxygen. This contrasts with the behavior of polyelectrolyte solns., which are almost nonfluorescent and do not evidence triplet state generation at the same P/D ratio.
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    Rodríguez, H. B.; Lagorio, M. G.; San Roman, E. Rose Bengal adsorbed on microgranular cellulose: evidence on fluorescent dimers Photochem. Photobiol. Sci. 2004, 3, 674– 680 DOI: 10.1039/B402484B
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    Rose Bengal adsorbed on microgranular cellulose: evidence on fluorescent dimers
    Rodriguez, Hernan B.; Lagorio, M. Gabriela; San Roman, Enrique
    Photochemical & Photobiological Sciences (2004), 3 (7), 674-680CODEN: PPSHCB; ISSN:1474-905X. (Royal Society of Chemistry)
    Rose Bengal adsorbed on microgranular cellulose was studied in the solid phase by total and diffuse reflectance and steady-state emission spectroscopy. A simple self-assocn. monomer-dimer equil. fitted reflectance data up to dye loadings of 4 × 10-7 mol (g cellulose)-1 and allowed calcn. of monomer and dimer spectra. Further increase of dye loading resulted in the formation of higher aggregates. Obsd. emission and excitation spectra and quantum yields were cor. for reabsorption and reemission of luminescence, using a previously developed model, within the assumption that only monomers are luminescent. An apparent increase of fluorescence quantum yield with dye loading was found, which was attributed to the occurrence of dimer fluorescence. Extension of the model to two luminescent species (i.e. monomer and dimer) yielded const. fluorescence quantum yields for the monomer, ΦM = 0.120 ± 0.004, and for the dimer, ΦD = 0.070 ± 0.006. The monomer quantum yield is close to the value found for the same dye in basic ethanol. The presence of fluorescent dimers and calcd. quantum yields are supported by anal. of the excitation spectra and other exptl. evidence. The possible occurrence of non-radiative energy transfer and the effect of surface charge on the properties of the dimer are analyzed.
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    Lissi, E. A.; Encinas, M. V.; Lemp, E.; Rubio, M. A. Singlet oxygen O2(1.DELTA.g) bimolecular processes. Solvent and compartmentalization effects Chem. Rev. 1993, 93, 699– 723 DOI: 10.1021/cr00018a004
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    Singlet oxygen O2(1Δg) bimolecular processes. Solvent and compartmentalization effects
    Lissi, E. A.; Encinas, M. V.; Lemp, E.; Rubio, M. A.
    Chemical Reviews (Washington, DC, United States) (1993), 93 (2), 699-723CODEN: CHREAY; ISSN:0009-2665.
    A review with >401 refs. including (1) deactivation dominated by energy transfer, (2) dyes and sensitizers, (3) inorg. anions, (4) N-contg. compds., (5) S-contg. compds., (6) unsatd. compds., and (7) microheterogeneous systems.
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    Alarcón, E.; Edwards, A. M.; Aspee, A.; Moran, F. E.; Borsarelli, C. D.; Lissi, E. A.; Gonzalez-Nilo, D.; Poblete, H.; Scaiano, J. C. Photophysics and photochemistry of dyes bound to human serum albumin are determined by the dye localization Photochem. Photobiol. Sci. 2010, 9, 93– 102 DOI: 10.1039/B9PP00091G
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    Photophysics and photochemistry of dyes bound to human serum albumin are determined by the dye localization
    Alarcon, Emilio; Edwards, Ana Maria; Aspee, Alexis; Moran, Faustino E.; Borsarelli, Claudio D.; Lissi, Eduardo A.; Gonzalez-Nilo, Danilo; Poblete, Horacio; Scaiano, J. C.
    Photochemical & Photobiological Sciences (2010), 9 (1), 93-102CODEN: PPSHCB; ISSN:1474-905X. (Royal Society of Chemistry)
    The photophysics and photochem. of rose bengal (RB) and methylene blue (MB) bound to human serum albumin (HSA) have been investigated under a variety of exptl. conditions. Distribution of the dyes between the external solvent and the protein has been estd. by phys. sepn. and fluorescence measurements. The main localization of protein-bound dye mols. was estd. by the intrinsic fluorescence quenching, displacement of fluorescent probes bound to specific protein sites, and by docking modeling. All the data indicate that, at low occupation nos., RB binds strongly to the HSA site I, while MB localizes predominantly in the protein binding site II. This different localization explains the obsd. differences in the dyes' photochem. behavior. In particular, the environment provided by site I is less polar and considerably less accessible to oxygen. The localization of RB in site I also leads to an efficient quenching of the intrinsic protein fluorescence (ascribed to the nearby Trp residue) and the generation of intra-protein singlet oxygen, whose behavior is different to that obsd. in the external solvent or when it is generated by bound MB.
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    Mills, A.; Lawrence, C.; Douglas, P. Photoreduction of Water sensitised by Rose Bengal J. Chem. Soc., Faraday Trans. 2 1986, 82, 2291– 2303 DOI: 10.1039/f29868202291
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    Photoreduction of water sensitized by Rose Bengal
    Mills, Andrew; Lawrence, Carl; Douglas, Peter
    Journal of the Chemical Society, Faraday Transactions 2: Molecular and Chemical Physics (1986), 82 (12), 2291-303CODEN: JCFTBS; ISSN:0300-9238.
    Rose Bengal was used to sensitize the photoredn. of H2O in aq. EtOH soln. (5% EtOH vol./vol.; ph 4.4) via both a reductive and an oxidative quenching mechanism, using EDTA and methylviologen, resp., as quenchers of its triplet state. In the presence of EDTA (which acts as both triplet quencher and sacrificial electron donor) the photoredn. of H2O sensitized by Rose Bengal was inefficient for a no. of reasons, including a low triplet quenching rate const. (8 × 103 dm3 mol-1 s-1) and a rapid disproportionation reaction involving the protonated semi-reduced dye radicals. In the presence of methylviologen (triplet quencher) and EDTA (sacrificial electron donor) the photoredn. of H2O sensitized by Rose Bengal was inefficient due to a low cage-escape yield (.vphi. ≈ 5 × 10-2) following the primary electron-transfer step, a fast back reaction (k ≥ 1 × 108 dm3 mol-1 s-1) and formation of a complex between the dye and methylviologen (K = 6400 ± 300 cm3 mol-). The complexed form of Rose Bengal appeared able to photosensitize, inefficiently, the photoredn. of methylviologen in the presence of EDTA, without exhibiting problems of dye fade.
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    Pupkaite, J.; Ahumada, M.; McLaughlin, S.; Temkit, M.; Alaziz, S.; Seymour, R.; Ruel, M.; Kochevar, I.; Griffith, M.; Suuronen, E. J.; Alarcon, E. I. Collagen-Based Photoactive Agent for Tissue Bonding ACS Appl. Mater. Interfaces 2017, 9, 9265– 9270 DOI: 10.1021/acsami.7b01984
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    Collagen-Based Photoactive Agent for Tissue Bonding
    Pupkaite, Justina; Ahumada, Manuel; Mclaughlin, Sarah; Temkit, Maha; Alaziz, Sura; Seymour, Richard; Ruel, Marc; Kochevar, Irene; Griffith, May; Suuronen, Erik J.; Alarcon, Emilio I.
    ACS Applied Materials & Interfaces (2017), 9 (11), 9265-9270CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)
    Using a combination of methacrylated collagen and the photosensitizer rose Bengal, a new light-activated biomimetic material for tissue sutureless bonding was developed. This formulation was crosslinked using green light. In vivo tests in mice demonstrate the suitability of the material for sutureless wound closure.
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    Henderson, B. W.; Busch, T. M.; Vaughan, L. A.; Frawley, N. P.; Babich, D.; Sosa, T. A.; Zollo, J. D.; Dee, A. S.; Cooper, M. T.; Bellnier, D. A.; Greco, W. R.; Oseroff, A. R. Photofrin photodynamic therapy can significantly deplete or preserve oxygenation in human basal cell carcinomas during treatment, depending on fluence rate Cancer Res. 2000, 60, 525– 529
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    Photofrin photodynamic therapy can significantly deplete or preserve oxygenation in human basal cell carcinomas during treatment, depending on fluence rate
    Henderson, Barbara W.; Busch, Theresa M.; Vaughan, Lurine A.; Frawley, Noreen P.; Babich, Debra; Sosa, Tara A.; Zollo, Joseph D.; Dee, Anthony S.; Cooper, Michele T.; Bellnier, David A.; Greco, William R.; Oseroff, Allan R.
    Cancer Research (2000), 60 (3), 525-529CODEN: CNREA8; ISSN:0008-5472. (AACR Subscription Office)
    At high fluence rates in animal models, photodynamic therapy (PDT) can photochem. deplete ambient tumor oxygen through the generation of singlet oxygen, causing acute hypoxia and limiting treatment effectiveness. We report that std. clin. treatment conditions (1 mg/kg Photofrin, light at 630 nm and 150 mW/cm2), which are highly effective for treating human basal cell carcinomas, significantly diminished tumor oxygen levels during initial light delivery in a majority of carcinomas. Oxygen depletion could be found during at least 40% of the total light dose, but tumors appeared well oxygenated toward the end of treatment. In contrast, initial light delivery at a lower fluence rate of 30 mW/cm2 increased tumor oxygenation in a majority of carcinomas. Laser treatment caused an intensity- and treatment time-dependent increase in tumor temp. The data suggest that high fluence rate treatment, although effective, may be inefficient.
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    Ravichandran, R.; Islam, M. M.; Alarcon, E. I.; Samanta, A.; Wang, S.; Lundstrom, P.; Hilborn, J.; Griffith, M.; Phopase, J. Functionalised type-I collagen as a hydrogel building block for bio-orthogonal tissue engineering applications J. Mater. Chem. B. 2016, 4, 318– 326 DOI: 10.1039/C5TB02035B
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    Functionalised type-I collagen as a hydrogel building block for bio-orthogonal tissue engineering applications
    Ravichandran, R.; Islam, M. M.; Alarcon, E. I.; Samanta, A.; Wang, S.; Lundstroem, P.; Hilborn, J.; Griffith, M.; Phopase, J.
    Journal of Materials Chemistry B: Materials for Biology and Medicine (2016), 4 (2), 318-326CODEN: JMCBDV; ISSN:2050-7518. (Royal Society of Chemistry)
    In this study, we derivatized type I collagen without altering its triple helical conformation to allow for facile hydrogel formation via the Michael addn. of thiols to methacrylates without the addn. of other crosslinking agents. This method provides the flexibility needed for the fabrication of injectable hydrogels or pre-fabricated implantable scaffolds, using the same components by tuning the modulus from Pa to kPa. Enzymic degradability of the hydrogels can also be easily fine-tuned by variation of the ratio and the type of the crosslinking component. The structural morphol. reveals a lamellar structure mimicking native collagen fibrils. The versatility of this material is demonstrated by its use as a pre-fabricated substrate for culturing human corneal epithelial cells and as an injectable hydrogel for 3-D encapsulation of cardiac progenitor cells.
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    Biasini, M.; Bienert, S.; Waterhouse, A.; Arnold, K.; Studer, G.; Schmidt, T.; Kiefer, F.; Gallo Cassarino, T.; Bertoni, M.; Bordoli, L.; Schwede, T. SWISS-MODEL: modelling protein tertiary and quaternary structure using evolutionary information Nucleic Acids Res. 2014, 42, W252– W258 DOI: 10.1093/nar/gku340
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    SWISS-MODEL: modelling protein tertiary and quaternary structure using evolutionary information
    Biasini, Marco; Bienert, Stefan; Waterhouse, Andrew; Arnold, Konstantin; Studer, Gabriel; Schmidt, Tobias; Kiefer, Florian; Cassarino, Tiziano Gallo; Bertoni, Martino; Bordoli, Lorenza; Schwede, Torsten
    Nucleic Acids Research (2014), 42 (W1), W252-W258CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)
    Protein structure homol. modeling has become a routine technique to generate 3D models for proteins when exptl. structures are not available. Fully automated servers such as SWISS-MODEL with user-friendly web interfaces generate reliable models without the need for complex software packages or downloading large databases. Here, we describe the latest version of the SWISS-MODEL expert system for protein structure modeling. The SWISS-MODEL template library provides annotation of quaternary structure and essential ligands and co-factors to allow for building of complete structural models, including their oligomeric structure. The improved SWISS-MODEL pipeline makes extensive use of model quality estn. for selection of the most suitable templates and provides ests. of the expected accuracy of the resulting models. The accuracy of the models generated by SWISS-MODEL is continuously evaluated by the CAMEO system. The new web site allows users to interactively search for templates, cluster them by sequence similarity, structurally compare alternative templates and select the ones to be used for model building. In cases where multiple alternative template structures are available for a protein of interest, a user-guided template selection step allows building models in different functional states. SWISS-MODEL is available at http://swissmodel.expasy.org/.
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    Vanommeslaeghe, K.; Hatcher, E.; Acharya, C.; Kundu, S.; Zhong, S.; Shim, J.; Darian, E.; Guvench, O.; Lopes, P.; Vorobyov, I.; Mackerell, A. D., Jr. CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields J. Comput. Chem. 2010, 31, 671– 690 DOI: 10.1002/jcc.21367
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    CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields
    Vanommeslaeghe, K.; Hatcher, E.; Acharya, C.; Kundu, S.; Zhong, S.; Shim, J.; Darian, E.; Guvench, O.; Lopes, P.; Vorobyov, I.; Mackerell, A. D., Jr.
    Journal of Computational Chemistry (2010), 31 (4), 671-690CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)
    The widely used CHARMM additive all-atom force field includes parameters for proteins, nucleic acids, lipids, and carbohydrates. In the present article, an extension of the CHARMM force field to drug-like mols. is presented. The resulting CHARMM General Force Field (CGenFF) covers a wide range of chem. groups present in biomols. and drug-like mols., including a large no. of heterocyclic scaffolds. The parametrization philosophy behind the force field focuses on quality at the expense of transferability, with the implementation concg. on an extensible force field. Statistics related to the quality of the parametrization with a focus on exptl. validation are presented. Addnl., the parametrization procedure, described fully in the present article in the context of the model systems, pyrrolidine, and 3-phenoxymethyl-pyrrolidine will allow users to readily extend the force field to chem. groups that are not explicitly covered in the force field as well as add functional groups to and link together mols. already available in the force field. CGenFF thus makes it possible to perform "all-CHARMM" simulations on drug-target interactions thereby extending the utility of CHARMM force fields to medicinally relevant systems. © 2009 Wiley Periodicals, Inc.J Comput Chem, 2010.
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    Vanommeslaeghe, K.; MacKerell, A. D., Jr. Automation of the CHARMM General Force Field (CGenFF) I: bond perception and atom typing J. Chem. Inf. Model. 2012, 52, 3144– 3154 DOI: 10.1021/ci300363c
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    Automation of the CHARMM General Force Field (CGenFF) I: Bond Perception and Atom Typing
    Vanommeslaeghe, K.; MacKerell, A. D.
    Journal of Chemical Information and Modeling (2012), 52 (12), 3144-3154CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)
    Mol. mechanics force fields are widely used in computer-aided drug design for the study of drug-like mols. alone or interacting with biol. systems. In simulations involving biol. macromols., the biol. part is typically represented by a specialized biomol. force field, while the drug is represented by a matching general (org.) force field. In order to apply these general force fields to an arbitrary drug-like mol., functionality for assignment of atom types, parameters, and charges is required. In the present article, which is part I of a series of two, we present the algorithms for bond perception and atom typing for the CHARMM General Force Field (CGenFF). The CGenFF atom typer first assocs. attributes to the atoms and bonds in a mol., such as valence, bond order, and ring membership among others. Of note are a no. of features that are specifically required for CGenFF. This information is then used by the atom typing routine to assign CGenFF atom types based on a programmable decision tree. This allows for straight-forward implementation of CGenFF's complicated atom typing rules and for equally straight-forward updating of the atom typing scheme as the force field grows. The presented atom typer was validated by assigning correct atom types on 477 model compds. including in the training set as well as 126 test-set mols. that were constructed to specifically verify its different components. The program may be utilized via an online implementation at https://www.paramchem.org/.
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    Vanommeslaeghe, K.; Raman, E. P.; MacKerell, A. D., Jr. Automation of the CHARMM General Force Field (CGenFF) II: assignment of bonded parameters and partial atomic charges J. Chem. Inf. Model. 2012, 52, 3155– 3168 DOI: 10.1021/ci3003649
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    Automation of the CHARMM General Force Field (CGenFF) II: Assignment of Bonded Parameters and Partial Atomic Charges
    Vanommeslaeghe, K.; Raman, E. Prabhu; MacKerell, A. D.
    Journal of Chemical Information and Modeling (2012), 52 (12), 3155-3168CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)
    Mol. mechanics force fields are widely used in computer-aided drug design for the study of drug candidates interacting with biol. systems. In these simulations, the biol. part is typically represented by a specialized biomol. force field, while the drug is represented by a matching general (org.) force field. In order to apply these general force fields to an arbitrary drug-like mol., functionality for assignment of atom types, parameters, and partial at. charges is required. In the present article, algorithms for the assignment of parameters and charges for the CHARMM General Force Field (CGenFF) are presented. These algorithms rely on the existing parameters and charges that were detd. as part of the parametrization of the force field. Bonded parameters are assigned based on the similarity between the atom types that define said parameters, while charges are detd. using an extended bond-charge increment scheme. Charge increments were optimized to reproduce the charges on model compds. that were part of the parametrization of the force field. Case studies are presented to clarify the functioning of the algorithms and the significance of their output data.
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    Best, R. B.; Zhu, X.; Shim, J.; Lopes, P. E.; Mittal, J.; Feig, M.; Mackerell, A. D., Jr. Optimization of the additive CHARMM all-atom protein force field targeting improved sampling of the backbone phi, psi and side-chain chi(1) and chi(2) dihedral angles J. Chem. Theory. Comput. 2012, 8, 3257– 3273 DOI: 10.1021/ct300400x
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    Optimization of the Additive CHARMM All-Atom Protein Force Field Targeting Improved Sampling of the Backbone .vphi., ψ and Side-Chain χ1 and χ2 Dihedral Angles
    Best, Robert B.; Zhu, Xiao; Shim, Jihyun; Lopes, Pedro E. M.; Mittal, Jeetain; Feig, Michael; MacKerell, Alexander D.
    Journal of Chemical Theory and Computation (2012), 8 (9), 3257-3273CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)
    While the quality of the current CHARMM22/CMAP additive force field for proteins has been demonstrated in a large no. of applications, limitations in the model with respect to the equil. between the sampling of helical and extended conformations in folding simulations have been noted. To overcome this, as well as make other improvements in the model, we present a combination of refinements that should result in enhanced accuracy in simulations of proteins. The common (non-Gly, -Pro) backbone CMAP potential has been refined against exptl. soln. NMR data for weakly structured peptides, resulting in a rebalancing of the energies of the α-helix and extended regions of the Ramachandran map, correcting the α-helical bias of CHARMM22/CMAP. The Gly and Pro CMAPs have been refitted to more accurate quantum-mech. energy surfaces. Side-chain torsion parameters have been optimized by fitting to backbone-dependent quantum-mech. energy surfaces, followed by addnl. empirical optimization targeting NMR scalar couplings for unfolded proteins. A comprehensive validation of the revised force field was then performed against a collection of exptl. data: (i) comparison of simulations of eight proteins in their crystal environments with crystal structures; (ii) comparison with backbone scalar couplings for weakly structured peptides; (iii) comparison with NMR residual dipolar couplings and scalar couplings for both backbone and side-chains in folded proteins; (iv) equil. folding of mini-proteins. The results indicate that the revised CHARMM 36 parameters represent an improved model for modeling and simulation studies of proteins, including studies of protein folding, assembly, and functionally relevant conformational changes.
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    Phillips, J. C.; Braun, R.; Wang, W.; Gumbart, J.; Tajkhorshid, E.; Villa, E.; Chipot, C.; Skeel, R. D.; Kale, L.; Schulten, K. Scalable molecular dynamics with NAMD J. Comput. Chem. 2005, 26, 1781– 1802 DOI: 10.1002/jcc.20289
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    Scalable molecular dynamics with NAMD
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    Journal of Computational Chemistry (2005), 26 (16), 1781-1802CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)
    NAMD is a parallel mol. dynamics code designed for high-performance simulation of large biomol. systems. NAMD scales to hundreds of processors on high-end parallel platforms, as well as tens of processors on low-cost commodity clusters, and also runs on individual desktop and laptop computers. NAMD works with AMBER and CHARMM potential functions, parameters, and file formats. This article, directed to novices as well as experts, first introduces concepts and methods used in the NAMD program, describing the classical mol. dynamics force field, equations of motion, and integration methods along with the efficient electrostatics evaluation algorithms employed and temp. and pressure controls used. Features for steering the simulation across barriers and for calcg. both alchem. and conformational free energy differences are presented. The motivations for and a roadmap to the internal design of NAMD, implemented in C++ and based on Charm++ parallel objects, are outlined. The factors affecting the serial and parallel performance of a simulation are discussed. Finally, typical NAMD use is illustrated with representative applications to a small, a medium, and a large biomol. system, highlighting particular features of NAMD, for example, the Tcl scripting language. The article also provides a list of the key features of NAMD and discusses the benefits of combining NAMD with the mol. graphics/sequence anal. software VMD and the grid computing/collab. software BioCoRE. NAMD is distributed free of charge with source code at www.ks.uiuc.edu.
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    Journal of Physical Chemistry B (1998), 102 (18), 3586-3616CODEN: JPCBFK; ISSN:1089-5647. (American Chemical Society)
    New protein parameters are reported for the all-atom empirical energy function in the CHARMM program. The parameter evaluation was based on a self-consistent approach designed to achieve a balance between the internal (bonding) and interaction (nonbonding) terms of the force field and among the solvent-solvent, solvent-solute, and solute-solute interactions. Optimization of the internal parameters used exptl. gas-phase geometries, vibrational spectra, and torsional energy surfaces supplemented with ab initio results. The peptide backbone bonding parameters were optimized with respect to data for N-methylacetamide and the alanine dipeptide. The interaction parameters, particularly the at. charges, were detd. by fitting ab initio interaction energies and geometries of complexes between water and model compds. that represented the backbone and the various side chains. In addn., dipole moments, exptl. heats and free energies of vaporization, solvation and sublimation, mol. vols., and crystal pressures and structures were used in the optimization. The resulting protein parameters were tested by applying them to noncyclic tripeptide crystals, cyclic peptide crystals, and the proteins crambin, bovine pancreatic trypsin inhibitor, and carbonmonoxy myoglobin in vacuo and in a crystal. A detailed anal. of the relationship between the alanine dipeptide potential energy surface and calcd. protein φ, χ angles was made and used in optimizing the peptide group torsional parameters. The results demonstrate that use of ab initio structural and energetic data by themselves are not sufficient to obtain an adequate backbone representation for peptides and proteins in soln. and in crystals. Extensive comparisons between mol. dynamics simulation and exptl. data for polypeptides and proteins were performed for both structural and dynamic properties. Calcd. data from energy minimization and dynamics simulations for crystals demonstrate that the latter are needed to obtain meaningful comparisons with exptl. crystal structures. The presented parameters, in combination with the previously published CHARMM all-atom parameters for nucleic acids and lipids, provide a consistent set for condensed-phase simulations of a wide variety of mols. of biol. interest.
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    A new method for performing mol. dynamics simulations under const. pressure is presented. In the method, which is based on the extended system formalism introduced by Andersen, the deterministic equations of motion for the piston degree of freedom are replaced by a Langevin equation; a suitable choice of collision frequency then eliminates the unphys. "ringing" of the vol. assocd. with the piston mass. In this way it is similar to the "weak coupling algorithm" developed by Berendsen and co-workers to perform mol. dynamics simulation without piston mass effects. It is shown, however, that the weak coupling algorithm induces artifacts into the simulation which can be quite severe for inhomogeneous systems such as aq. biopolymers or liq./liq. interfaces.
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    An N·log(N) method for evaluating electrostatic energies and forces of large periodic systems is presented. The method is based on interpolation of the reciprocal space Ewald sums and evaluation of the resulting convolution using fast Fourier transforms. Timings and accuracies are presented for three large cryst. ionic systems.
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    An algorithm, called RATTLE, for integrating the equations of motion in mol. dynamics calcns. for mol. models with internal constraints is presented. RATTLE calcs. the positions and velocities at the next time from the positions and velocities at the present time step, without requiring information about the earlier history. It is based on the Verlet algorithm and retains the simplicity of using Cartesian coordinates for each of the atoms to describe the configuration of a mol. with internal constraints. RATTLE guarantees that the coordinates and velocities of the atoms in a mol. satisfy the internal constraints at each time step.
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    Hopkins, C. W.; Le Grand, S.; Walker, R. C.; Roitberg, A. E. Long-Time-Step Molecular Dynamics through Hydrogen Mass Repartitioning J. Chem. Theory Comput. 2015, 11, 1864– 1874 DOI: 10.1021/ct5010406
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    Hopkins, Chad W.; Le Grand, Scott; Walker, Ross C.; Roitberg, Adrian E.
    Journal of Chemical Theory and Computation (2015), 11 (4), 1864-1874CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)
    Previous studies have shown that the method of hydrogen mass repartitioning (HMR) is a potentially useful tool for accelerating mol. dynamics (MD) simulations. By repartitioning the mass of heavy atoms into the bonded hydrogen atoms, it is possible to slow the highest-frequency motions of the macromol. under study, thus allowing the time step of the simulation to be increased by up to a factor of 2. In this communication, we investigate further how this mass repartitioning allows the simulation time step to be increased in a stable fashion without significantly increasing discretization error. To this end, we ran a set of simulations with different time steps and mass distributions on a three-residue peptide to get a comprehensive view of the effect of mass repartitioning and time step increase on a system whose accessible phase space is fully explored in a relatively short amt. of time. We next studied a 129-residue protein, hen egg white lysozyme (HEWL), to verify that the obsd. behavior extends to a larger, more-realistic, system. Results for the protein include structural comparisons from MD trajectories, as well as comparisons of pKa calcns. via const.-pH MD. We also calcd. a potential of mean force (PMF) of a dihedral rotation for the MTS [(1-oxyl-2,2,5,5-tetramethyl-pyrroline-3-methyl)methanethiosulfonate] spin label via umbrella sampling with a set of regular MD trajectories, as well as a set of mass-repartitioned trajectories with a time step of 4 fs. Since no significant difference in kinetics or thermodn. is obsd. by the use of fast HMR trajectories, further evidence is provided that long-time-step HMR MD simulations are a viable tool for accelerating MD simulations for mols. of biochem. interest.
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    Using collective variables to drive molecular dynamics simulations
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    Molecular Physics (2013), 111 (22-23), 3345-3362CODEN: MOPHAM; ISSN:0026-8976. (Taylor & Francis Ltd.)
    A software framework is introduced that facilitates the application of biasing algorithms to collective variables of the type commonly employed to drive massively parallel mol. dynamics (MD) simulations. The modular framework that is presented enables one to combine existing collective variables into new ones, and combine any chosen collective variable with available biasing methods. The latter include the classic time-dependent biases referred to as steered MD and targeted MD, the temp.-accelerated MD algorithm, as well as the adaptive free-energy biases called metadynamics and adaptive biasing force. The present modular software is extensible, and portable between commonly used MD simulation engines.
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    Comer, J.; Gumbart, J. C.; Hénin, J.; Lelièvre, T.; Pohorille, A.; Chipot, C. The Adaptive Biasing Force Method: Everything You Always Wanted To Know but Were Afraid To Ask J. Phys. Chem. B 2015, 119, 1129– 1151 DOI: 10.1021/jp506633n
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    The Adaptive Biasing Force Method: Everything You Always Wanted To Know but Were Afraid To Ask
    Comer, Jeffrey; Gumbart, James C.; Henin, Jerome; Lelievre, Tony; Pohorille, Andrew; Chipot, Christophe
    Journal of Physical Chemistry B (2015), 119 (3), 1129-1151CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
    In the host of numerical schemes devised to calc. free energy differences by way of geometric transformations, the adaptive biasing force algorithm has emerged as a promising route to map complex free-energy landscapes. It relies upon the simple concept that as a simulation progresses, a continuously updated biasing force is added to the equations of motion, such that in the long-time limit it yields a Hamiltonian devoid of an av. force acting along the transition coordinate of interest. This means that sampling proceeds uniformly on a flat free-energy surface, thus providing reliable free-energy ests. Much of the appeal of the algorithm to the practitioner is in its phys. intuitive underlying ideas and the absence of any requirements for prior knowledge about free-energy landscapes. Since its inception in 2001, the adaptive biasing force scheme has been the subject of considerable attention, from in-depth math. anal. of convergence properties to novel developments and extensions. The method has also been successfully applied to many challenging problems in chem. and biol. In this contribution, the method is presented in a comprehensive, self-contained fashion, discussing with a crit. eye its properties, applicability, and inherent limitations, as well as introducing novel extensions. Through free-energy calcns. of prototypical mol. systems, many methodol. aspects are examd., from stratification strategies to overcoming the so-called hidden barriers in orthogonal space, relevant not only to the adaptive biasing force algorithm but also to other importance-sampling schemes. On the basis of the discussions in this paper, a no. of good practices for improving the efficiency and reliability of the computed free-energy differences are proposed.
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    Adaptive biasing force method for scalar and vector free energy calculations
    Darve, Eric; Rodriguez-Gomez, David; Pohorille, Andrew
    Journal of Chemical Physics (2008), 128 (14), 144120/1-144120/13CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)
    In free energy calcns. based on thermodn. integration, it is necessary to compute the derivs. of the free energy as a function of one (scalar case) or several (vector case) order parameters. We derive in a compact way a general formulation for evaluating these derivs. as the av. of a mean force acting on the order parameters, which involves first derivs. with respect to both Cartesian coordinates and time. This is in contrast with the previously derived formulas, which require first and second derivs. of the order parameter with respect to Cartesian coordinates. As illustrated in a concrete example, the main advantage of this new formulation is the simplicity of its use, esp. for complicated order parameters. It is also straightforward to implement in a mol. dynamics code, as can be seen from the pseudo-code given at the end. We further discuss how the approach based on time derivs. can be combined with the adaptive biasing force method, an enhanced sampling technique that rapidly yields uniform sampling of the order parameters, and by doing so greatly improves the efficiency of free energy calcns. Using the backbone dihedral angles Φ and Ψ in N-acetylalanyl-N'-methylamide as a numerical example, we present a technique to reconstruct the free energy from its derivs., a calcn. that presents some difficulties in the vector case because of the statistical errors affecting the derivs. (c) 2008 American Institute of Physics.
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    Overcoming free energy barriers using unconstrained molecular dynamics simulations
    Henin, Jerome; Chipot, Christophe
    Journal of Chemical Physics (2004), 121 (7), 2904-2914CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)
    Assocn. of unconstrained mol. dynamics (MD) and the formalisms of thermodn. integration and av. force [Darve and Pohorille, J. Chem. Phys. 115, 9169 (2001)] have been employed to det. potentials of mean force. When implemented in a general MD code, the addnl. computational effort, compared to other std., unconstrained simulations, is marginal. The force acting along a chosen reaction coordinate ξ is estd. from the individual forces exerted on the chem. system and accumulated as the simulation progresses. The estd. free energy deriv. computed for small intervals of ξ is canceled by an adaptive bias to overcome the barriers of the free energy landscape. Evolution of the system along the reaction coordinate is, thus, limited by its sole self-diffusion properties. The illustrative examples of the reversible unfolding of deca-L-alanine, the assocn. of acetate and guanidinium ions in water, the dimerization of methane in water, and its transfer across the water liq.-vapor interface are examd. to probe the efficiency of the method.
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  15. Roberto Rosales-Rojas, Matías Zuñiga-Bustos, Francisca Salas-Sepúlveda, Constanza Galaz-Araya, Ricardo A. Zamora, Horacio Poblete. Self-Organization Dynamics of Collagen-like Peptides Crosslinking Is Driven by Rose-Bengal-Mediated Electrostatic Bridges. Pharmaceutics 2022, 14 (6) , 1148. https://doi.org/10.3390/pharmaceutics14061148
  16. Chengfeng Cai, Jing-Ju Huang, Koki Sano, Yicheng Zhu, Yunhua Zhang, Qing Wu, Bo Zhu, Yasuhiro Ishida, Shyh-Chyang Luo, Hsing-An Lin. A water-soluble corannulene with highly efficient ROS production. Materials Chemistry and Physics 2022, 281 , 125885. https://doi.org/10.1016/j.matchemphys.2022.125885
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  26. Keun Ah Ryu, Christina M. Kaszuba, Noah B. Bissonnette, Rob C. Oslund, Olugbeminiyi O. Fadeyi. Interrogating biological systems using visible-light-powered catalysis. Nature Reviews Chemistry 2021, 5 (5) , 322-337. https://doi.org/10.1038/s41570-021-00265-6
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  37. Robert D. Bongard, Michael Lepley, Adam Gastonguay, Raulia R. Syrlybaeva, Marat R. Talipov, Rachel A. Jones Lipinski, Noah R. Leigh, Jaladhi Brahmbhatt, Raman Kutty, Rajendra Rathore, Ramani Ramchandran, Daniel S. Sem. Discovery and characterization of halogenated xanthene inhibitors of DUSP5 as potential photodynamic therapeutics. Journal of Photochemistry and Photobiology A: Chemistry 2019, 375 , 114-131. https://doi.org/10.1016/j.jphotochem.2019.01.005
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  • Abstract

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    Figure 1

    Figure 1. Effect of collagen-like peptide on 10 μM rose Bengal absorption. (a) Spectral changes and (b) changes in the absorption at RB monomer maximum 550 nm and at 570 nm, the maximum of the red-shifted peak for aggregated RB bound to CLP, plotted as a function of CLP concentration. All measurements were carried out in 10 mM MES buffer (pH 5.0).

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    Figure 2

    Figure 2. Right: Normalized absorption spectra for RB prepared at different dye concentrations incorporated within collagen matrices. Left: Normalized absorption spectra for RB measured in buffer solutions. All measurements were carried out in phosphate buffer pH 7.4 at room temperature.

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    Figure 3

    Figure 3. Molecular simulation of RB binding to the CLP. (a) Molecular model of RB in the charge state used in the simulations. The carboxylate and phenolate moieties each have charges of −1. Atom color code: H, white; C, cyan; O, red; Cl, green; I, purple. (b) Snapshot of a simulation of the CLP triple helix with one molecule of RB. The CLP is shown as a green tube, Na+ and Cl– ions are shown as yellow and cyan spheres. For clarity, the explicit water molecules are shown as a transparent surface. (c) Free-energy landscape for RB in the vicinity of the CLP triple helix at low RB concentration, calculated by the adaptive biasing force method. The potential of mean force is mapped as a function of the position of the RB molecule along the CLP axis (disZ) and distance from this axis (disXY). The geometric contribution to the free energy along disXY has been removed. (d) Free-energy landscape at a higher RB concentration calculated from a set of equilibrium simulations including a CLP triple helix and 20 RB molecules. (e) Snapshot from the simulation with 20 RB molecules.

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    Figure 4

    Figure 4. Molecular interactions between RB and CLP. (a) Electrostatic contact and H-bonding between the N-terminus of the CLP and the carboxylate group of RB. In these images, the phenolate (O–) group is highlighted by a red sphere to distinguish it from the carbonyl oxygen. Atoms are colored as in Figure 3, except that CLP carbons are colored dark green. H-bonds are indicated by dotted black lines. (b) Hydrophobic contact between the three-ring moiety of RB and a Pro residue of the CLP. (c) H-bonding between the O– group of RB and the backbone NH of the CLP, coupled with ionic contact between the O– group and a Lys side chain. (d) H-bonding between the OH group of hydroxyproline (Hyp) and the carboxylate group of RB. An ionic Lys–O– contact is also apparent. (e) The free-energy landscape of RB near the CLP with labels (a–d) indicating the location of RB in the corresponding panels of this figure. The ranges of disZ values occupied by the N-terminus and Asp, Hyp, and Lys side chains are also indicated. (f) The prevalence of H-bonding between RB and different groups of the CLP as a function of position along the CLP axis. Plotted are the number of H-bonds involving all CLP groups (CLP), backbone amide nitrogens (BB), N-terminal NH3+ groups (Nter), Hyp side chain OH groups, and Lys side chain NH3+ groups. (g) The prevalence of H-bonding between the CLP and different groups of RB as a function of position along the CLP axis.

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    Figure 5

    Figure 5. Photodecomposition of rose Bengal (125 μM) in the presence of arginine (25 mM). (a) Irradiation of rose Bengal in nitrogen saturated solution. (b) Absorption spectra (expanded scale) of rose Bengal samples irradiated for 7 min in the presence of 25 mM Arg in solutions saturated with oxygen, air, and nitrogen. All data collected in PBS buffer pH 7.4 at room temperature. Solutions irradiated at 532 nm, irradiance = 0.3 W/cm2. Results shown are from single irradiations in triplicate independent experiments.

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    Figure 6

    Figure 6. Photodegradation of 10 μM RB in the presence of different additives: (a) without and (b) with 2.5 μM collagen at RB/collagen (4:1). Left: Absorption spectra for RB measured in solution at different irradiation times. Right: Changes in absorption intensities measured at 550 nm, plotted as A/A0, for RB solutions recorded in the presence of different additives. All data collected in 10 mM MES buffer pH 5.0 at room temperature. Data correspond to the average calculated from three independent experiments each repeated in triplicate (n = 9).

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    Figure 7

    Figure 7. Photodegradation of 40 μM RB incorporated within collagen hydrogels prepared using type I collagen containing different additives. Left: Absorption spectra for the RB–collagen hydrogel composite measured at different irradiation times in an air atmosphere. Right: Changes in absorption intensities measured at 556 nm for RB solutions recorded in the presence of different additives [Azide: 10 mM, Trp: 2 mM, Arg: 10 mM]. All data collected in PBS buffer pH 7.4 at room temperature. Data correspond to the average calculated from three independent experiments each repeated in triplicate (n = 9).

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    Figure 8

    Figure 8. Triplet transient lifetime and quenching of RB embedded in collagen hydrogels in the presence of different quenchers. (a) RB triplet decay monitored at 620 nm measured in air (black circles) or nitrogen (blue circles) saturated solutions. Insets correspond to decay residuals obtained from the exponential fit for the decays shown in the figure. Measured lifetimes for: (b) RB triplet, (c) RB anion radical, and (d) singlet oxygen under different conditions or additives. Concentrations of additives were: tryptophan: 2.0 mM, Arg: 10 mM, and sodium azide: 10 mM. Effect of additives for laser flash photolysis experiments were carried out in nitrogen saturated solutions. For singlet oxygen measurements, samples were equilibrated with air prior to laser excitation. Measurements for triplet and anion radical were carried out in 10 mM pH 5.0 MES buffer. For singlet oxygen phosphorescence, a 10 mM MES buffer was prepared with a pD of 5.0. In all cases, photodegradation was kept lower than 10%. Time traces correspond to the average of 12 separate decays from 3 independent samples.

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    This article references 51 other publications.

    1. 1
      Chan, B. P.; Amann, C.; Yaroslavsky, A. N.; Title, C.; Smink, D.; Zarins, B.; Kochevar, I. E.; Redmond, R. W. Photochemical repair of Achilles tendon rupture in a rat model J. Surg. Res. 2005, 124, 274– 279 DOI: 10.1016/j.jss.2004.09.019
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      Photochemical repair of Achilles tendon rupture in a rat model
      Chan, Barbara P.; Amann, Christopher; Yaroslavsky, Anna N.; Title, Craig; Smink, David; Zarins, Bertram; Kochevar, Irene E.; Redmond, Robert W.
      Journal of Surgical Research (2005), 124 (2), 274-279CODEN: JSGRA2; ISSN:0022-4804. (Elsevier)
      Photochem. tissue bonding (PTB) is an emerging technique for bonding or sealing tissue surfaces that requires light and a photoactive dye for its effect. The potential of PTB for tendon repair was assessed in a rat model. The optical properties of bovine tendon were detd. ex vivo to gauge the depth of light penetration as a function of wavelength and dosimetry parameters were established for PTB repair of ruptured tendon. PTB was then tested in vivo to repair transected tendons in Sprague-Dawley rats. Repair strengths were measured using a strain gauge up to 14 days post treatment. The effective penetration depth in tendon was estd. to be 0.68 mm at 514 nm. Following PTB treatment of mech. ruptured tendon, significant bonding was dependent on the presence of both light and dye and attained a plateau strength at a fluence of 125 J/cm2. In a subsequent in vivo study to investigate PTB for repair of transected rat Achilles tendon, the ultimate stress required to break the repaired tendon was measured immediately after irradn. and at 7 and 14 days post-repair. Results showed that the difference in the ultimate stress between control and PTB treatment groups was statistically significant immediately after treatment and at 7 days (p = 0.04) but not 14 days (p = 0.75) post-repair. PTB provides a benefit to tendon repair at early stages in repair and is worthy of further investigation as a potential surgical adjunct for tendon repair in orthopedic surgeries.
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      Fairbairn, N. G.; Ng-Glazier, J.; Meppelink, A. M.; Randolph, M. A.; Valerio, I. L.; Fleming, M. E.; Kochevar, I. E.; Winograd, J. M.; Redmond, R. W. Light-Activated Sealing of Acellular Nerve Allografts following Nerve Gap Injury J. Reconstr. Microsurg. 2016, 32, 421– 430 DOI: 10.1055/s-0035-1571247
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      Light-Activated Sealing of Acellular Nerve Allografts following Nerve Gap Injury
      Fairbairn Neil G; Ng-Glazier Joanna; Meppelink Amanda M; Randolph Mark A; Winograd Jonathan M; Valerio Ian L; Fleming Mark E; Kochevar Irene E; Redmond Robert W
      Journal of reconstructive microsurgery (2016), 32 (6), 421-30 ISSN:.
      Introduction Photochemical tissue bonding (PTB) uses visible light to create sutureless, watertight bonds between two apposed tissue surfaces stained with photoactive dye. In phase 1 of this two-phase study, nerve gaps repaired with bonded isografts were superior to sutured isografts. When autograft demand exceeds supply, acellular nerve allograft (ANA) is an alternative although outcomes are typically inferior. This study assesses the efficacy of PTB when used with ANA. Methods Overall 20 male Lewis rats had 15-mm left sciatic nerve gaps repaired using ANA. ANAs were secured using epineurial suture (group 1) or PTB (group 2). Outcomes were assessed using sciatic function index (SFI), gastrocnemius muscle mass retention, and nerve histomorphometry. Historical controls from phase 1 were used to compare the performance of ANA with isograft. Statistical analysis was performed using analysis of variance and Bonferroni all-pairs comparison. Results All ANAs had signs of successful regeneration. Mean values for SFI, muscle mass retention, nerve fiber diameter, axon diameter, and myelin thickness were not significantly different between ANA + suture and ANA + PTB. On comparative analysis, ANA + suture performed significantly worse than isograft + suture from phase 1. However, ANA + PTB was statistically comparable to isograft + suture, the current standard of care. Conclusion Previously reported advantages of PTB versus suture appear to be reduced when applied to ANA. The lack of Schwann cells and neurotrophic factors may be responsible. PTB may improve ANA performance to an extent, where they are equivalent to autograft. This may have important clinical implications when injuries preclude the use of autograft.
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    3. 3
      Mulroy, L.; Kim, J.; Wu, I.; Scharper, P.; Melki, S. A.; Azar, D. T.; Redmond, R. W.; Kochevar, I. E. Photochemical keratodesmos for repair of lamellar corneal incisions Invest. Ophthalmol. Visual Sci. 2000, 41, 3335– 3340
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    4. 4
      O’Neill, A. C.; Winograd, J. M.; Zeballos, J. L.; Johnson, T. S.; Randolph, M. A.; Bujold, K. E.; Kochevar, I. E.; Redmond, R. W. Microvascular anastomosis using a photochemical tissue bonding technique Lasers Surg. Med. 2007, 39, 716– 722 DOI: 10.1002/lsm.20548
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      4
      Microvascular anastomosis using a photochemical tissue bonding technique
      O'Neill Anne C; Winograd Jonathan M; Zeballos Jose L; Johnson T Shane; Randolph Mark A; Bujold Kenneth E; Kochevar Irene E; Redmond Robert W
      Lasers in surgery and medicine (2007), 39 (9), 716-22 ISSN:0196-8092.
      BACKGROUND AND OBJECTIVES: Photochemical tissue bonding (PTB) combines photoactive dyes with visible light to create fluid-tight seals between tissue surfaces without causing collateral thermal damage. The potential of PTB to improve outcomes over standard of care microsurgical reanastomoses of blood vessels in ex vivo and in vivo models was evaluated. STUDY DESIGN: The mechanical strength and integrity of PTB and standard microsurgical suture repairs in ex vivo porcine brachial arteries (n = 10) were compared using hydrostatic testing of leak point pressure (LPP). Femoral artery repair in vivo was measured in Sprague-Dawley rats using either standard microvascular sutures (n = 20) or PTB (n = 20). Patency was evaluated at 6 hours (n = 10) and 8 weeks post-repair (n = 10) for each group. RESULTS: PTB produced significantly higher LPPs (1,100+/- 150 mmHg) than suture repair (350+/-40 mmHg, P<0.001) in an ex vivo study. In an in vivo study all femoral arteries in both suture and PTB repair groups were patent at 6 hours post-repair. At 8 weeks post-repair the patency rate was 80% for both groups. No evidence of aneurysm formation was seen in either group and bleeding was absent from the repair site in the PTB-treated vessels, in contrast to the suture repair group. CONCLUSION: PTB is a feasible microvascular repair technique that results in an immediate, mechanically robust bond with short- and long-term patency rates equal to those for standard suture repair.
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    5. 5
      Senthil-Kumar, P.; Ni, T.; Randolph, M. A.; Velmahos, G. C.; Kochevar, I. E.; Redmond, R. W. A light-activated amnion wrap strengthens colonic anastomosis and reduces peri-anastomotic adhesions Lasers Surg. Med. 2016, 48, 530– 537 DOI: 10.1002/lsm.22507
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      A light-activated amnion wrap strengthens colonic anastomosis and reduces peri-anastomotic adhesions
      Senthil-Kumar Prabhu; Ni Tao; Kochevar Irene E; Redmond Robert W; Senthil-Kumar Prabhu; Randolph Mark A; Ni Tao; Velmahos George C
      Lasers in surgery and medicine (2016), 48 (5), 530-7 ISSN:.
      BACKGROUND AND OBJECTIVE: Colonic anastomotic failure is a dreaded complication, and multiple surgical techniques have failed to eliminate it. Photochemical tissue bonding (PTB) is a method of sealing tissue surfaces by light-activated crosslinking. We evaluated if a human amniotic membrane (HAM), sealed over the anastomotic line by PTB, increases the anastomotic strength. STUDY DESIGN: Sprague-Dawley rats underwent midline laparotomy followed by surgical transection of the left colon. Animals were randomized to colonic anastomosis by one of the following methods (20 per group): single-layer continuous circumferential suture repair (SR); SR with a HAM wrap attached by suture (SR+ HAM-S); SR with HAM bonded photochemically over the anastomotic site using 532 nm light (SR+ HAM-PTB); approximation of the bowel ends with only three sutures and sealing with HAM-PTB (3+ HAM-PTB). A control group underwent laparotomy alone with no colon resection (NR). Sub-groups (n = 10) were sacrificed at days 3 and 7 post-operatively and adhesions were evaluated. A 6 cm section of colon was then removed and strength of anastomosis evaluated by burst pressure (BP) measurement. RESULTS: A fourfold increase in BP was observed in the SR+ HAM-PTB group compared to suture repair alone (94 ± 3 vs. 25 ± 8 mm Hg, P < 0.0001) at day 3. At day 7 the burst pressures were 165 ± 40 and 145 ± 31 mm Hg (P = 1), respectively. A significant decrease in peri-anastomotic adhesions was observed in the SR+ HAM-PTB group compared to the SR group at both time points (P < 0.001). CONCLUSION: Sealing sutured colonic anastomotic lines with HAM-PTB increases the early strength of the repair and reduces peri-anastomotic adhesions. Lasers Surg. Med. 48:530-537, 2016. © 2016 Wiley Periodicals, Inc.
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    6. 6
      Tsao, S.; Yao, M.; Tsao, H.; Henry, F. P.; Zhao, Y.; Kochevar, J. J.; Redmond, R. W.; Kochevar, I. E. Light-activated tissue bonding for excisional wound closure: a split-lesion clinical trial Br. J. Dermatol. 2012, 166, 555– 563 DOI: 10.1111/j.1365-2133.2011.10710.x
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      6
      Light-activated tissue bonding for excisional wound closure: a split-lesion clinical trial
      Tsao S; Yao M; Tsao H; Henry F P; Zhao Y; Kochevar J J; Redmond R W; Kochevar I E
      The British journal of dermatology (2012), 166 (3), 555-63 ISSN:.
      BACKGROUND: Apposition of wound edges by sutures provides a temporary scaffold and tension support for healing. We have developed a novel tissue-sealing technology, photoactivated tissue bonding (PTB), which immediately crosslinks proteins between tissue planes, thereby sealing on a molecular scale. OBJECTIVES: To determine the effectiveness of PTB for superficial closure of skin excisions and to compare the results with standard epidermal suturing. METHODS: A split-lesion, paired comparison study of 31 skin excisions was performed. Following deep closure with absorbable sutures, one-half of each wound was superficially closed with nonabsorbable nylon sutures while the other half was stained with Rose Bengal dye and treated with green light. Overall appearance and scar characteristics were rated at 2weeks and 6months in a blinded manner by three dermatologists viewing photographs, by two onsite physicians and by patients. RESULTS: At 2weeks, neither sutured nor PTB-treated segments showed dehiscence; however, PTB-sealed segments showed less erythema than sutured segments as determined by photographic (P=0·001) and onsite evaluations (P=0·005). Overall appearance after PTB was judged better than after sutures (P=0·002). At 6months, scars produced by PTB were deemed superior to scars resulting from sutures in terms of appearance (P<0·001), width (P=0·002) and healing (P=0·003). Patients were more satisfied with the appearance of the PTB-sealed wound half after 2weeks and 6months (P=0·013 and P=0·003, respectively). CONCLUSIONS: A novel molecular suturing technique produces effective wound sealing and less scarring than closure with nylon interrupted epidermal sutures. Comparisons with better suturing techniques are warranted.
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    7. 7
      Verter, E. E.; Gisel, T. E.; Yang, P.; Johnson, A. J.; Redmond, R. W.; Kochevar, I. E. Light-initiated bonding of amniotic membrane to cornea Invest. Ophthalmol. Visual Sci. 2011, 52, 9470– 9477 DOI: 10.1167/iovs.11-7248
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      7
      Light-initiated bonding of amniotic membrane to cornea
      Verter, E. Eri; Gisel, Thomas E.; Yang, Penggao; Johnson, Anthony J.; Redmond, Robert W.; Kochevar, Irene E.
      Investigative Ophthalmology & Visual Science (2011), 52 (13), 9470-9477CODEN: IOVSDA; ISSN:1552-5783. (Association for Research in Vision and Ophthalmology)
      Purpose: Suturing amniotic membrane to cornea during surgery is time consuming, and sutures may further damage the eye. The authors introduce a novel sutureless, light-activated technique that securely attaches amnion to cornea through protein-protein crosslinks. Methods: Cryopreserved human amniotic membrane, stained with Rose Bengal (RB), was placed over a full-thickness wound in deepithelialized rabbit cornea and was treated with green laser. The intraocular pressure that broke the seal (IOPL) was measured, and adhesion was measured with a peel test. The influences on bonding strength of fluence, irradiance, RB concn., and amnion surface bonded were measured. Epithelial cell migration on treated amnion and keratocyte viability after bonding were also measured. The involvement in the bonding mechanism of oxygen, singlet oxygen, and assocn. of RB with stromal collagen was investigated. Results: Sealing amniotic membrane over cornea using 0.1% RB and 150 J/cm2 at 532 nm produced an IOPL of 261 ± 77 mm Hg ex vivo and 448 mm ± 212 mm Hg in vivo. The ex vivo IOPL increased with increasing fluence (50-150 J/cm2). Equivalent IOPL was produced for bonding basement membrane or stromal amnion surfaces. The bonding treatment was not toxic to keratocytes but slightly reduced the migration of corneal epithelial cells on amnion ex vivo. Mechanism studies indicated that RB forms two complexes with amnion stromal collagen, that bonding requires oxygen, and that singlet oxygen mediates protein crosslinking. Conclusions: A rapid, light-activated technique produces strong, immediate bonding between amnion and cornea and merits further evaluation for ocular surface surgeries.
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    8. 8
      Cherfan, D.; Verter, E. E.; Melki, S.; Gisel, T. E.; Doyle, F. J., Jr.; Scarcelli, G.; Yun, S. H.; Redmond, R. W.; Kochevar, I. E. Collagen cross-linking using rose bengal and green light to increase corneal stiffness Invest. Ophthalmol. Visual Sci. 2013, 54, 3426– 3433 DOI: 10.1167/iovs.12-11509
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    9. 9
      Zhu, H.; Alt, C.; Webb, R. H.; Melki, S.; Kochevar, I. E. Corneal Crosslinking With Rose Bengal and Green Light: Efficacy and Safety Evaluation Cornea 2016, 35, 1234– 1241 DOI: 10.1097/ICO.0000000000000916
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      There is no corresponding record for this reference.
    10. 10
      Goldstone, R. N.; McCormack, M. C.; Goldstein, R. L.; Mallidi, S.; Randolph, M. A.; Watkins, M. T.; Redmond, R. W.; Austen, W. G., Jr. Photochemical Tissue Passivation Attenuates AV Fistula Intimal HyperplasiaAnn. Surg. 2016,  DOI: 10.1097/SLA.0000000000002046 .
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      There is no corresponding record for this reference.
    11. 11
      Goldstone, R. N.; McCormack, M. C.; Khan, S. I.; Salinas, H. M.; Meppelink, A.; Randolph, M. A.; Watkins, M. T.; Redmond, R. W.; Austen, W. G., Jr. Photochemical Tissue Passivation Reduces Vein Graft Intimal Hyperplasia in a Swine Model of Arteriovenous Bypass Grafting J. Am. Heart Assoc. 2016, 5e003856 DOI: 10.1161/JAHA.116.003856
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      11
      Photochemical tissue passivation reduces vein graft intimal hyperplasia in a swine model of arteriovenous bypass grafting
      Goldstone, Robert N.; McCormack, Michael C.; Khan, Saiqa I.; Salinas, Harry M.; Meppelink, Amanda; Randolph, Mark A.; Watkins, Michael T.; Redmond, Robert W.; Austen, William G. Jr.
      Journal of the American Heart Association (2016), 5 (8), e003856/1-e003856/10CODEN: JAHABZ; ISSN:2047-9980. (Wiley-Blackwell)
      Background-Bypass grafting remains the std. of care for coronary artery disease and severe lower extremity ischemia. Efficacy is limited by poor long-term venous graft patency secondary to intimal hyperplasia (IH) caused by venous injury upon exposure to arterial pressure. We investigate whether photochem. tissue passivation (PTP) treatment of vein grafts modulates smooth muscle cell (SMC) proliferation and migration, and inhibits development of IH. Methods and Results-PTP was performed at increasing fluences up to 120 J/cm2 on porcine veins. Tensiometry performed to assess vessel elasticity/stiffness showed increased stiffness with increasing fluence until plateauing at 90 J/cm2 (median, interquartile range [IQR]). At 90 J/cm2, PTP-treated vessels had a 10-fold greater Young's modulus than untreated controls (954 [IQR, 2217] vs 99 kPa [IQR, 63]; P=0.03). Each pig received a PTP-treated and untreated carotid artery venous interposition graft. At 4-wk, intimal/medial areas were assessed. PTP reduced the degree of IH by 66% and medial hypertrophy by 49%. Intimal area was 3.91 (IQR, 1.2) and 1.3 mm2 (IQR, 0.97; P≤0.001) in untreated and PTP-treated grafts, resp. Medial area was 9.2 (IQR, 3.2) and 4.7 mm2 (IQR, 2.0; P≤0.001) in untreated and PTP-treated grafts, resp. Immunohistochem. was performed to assess alpha-smooth muscle actin (SMA) and proliferating cell nuclear antigen (PCNA). Objectively, there were less SMA-pos. cells within the intima/media of PTP-treated vessels than controls. There was an increase in PCNA-pos. cells within control vein grafts (18% [IQR, 5.3]) vs. PTP-treated vein grafts (5% [IQR, 0.9]; P=0.02). Conclusions-By strengthening vein grafts, PTP decreases SMC proliferation and migration, thereby reducing IH.
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    12. 12
      Fernandes, J. R.; Salinas, H. M.; Broelsch, G. F.; McCormack, M. C.; Meppelink, A. M.; Randolph, M. A.; Redmond, R. W.; Austen, W. G., Jr. Prevention of capsular contracture with photochemical tissue passivation Plast. Reconstr. Surg. 2014, 133, 571– 577 DOI: 10.1097/01.prs.0000438063.31043.79
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      12
      Prevention of Capsular Contracture with Photochemical Tissue Passivation
      Fernandes, Justin R.; Salinas, Harry M.; Broelsch, G. Felix; McCormack, Michael C.; Meppelink, Amanda M.; Randolph, Mark A.; Redmond, Robert W.; Austen, William G., Jr.
      Plastic and Reconstructive Surgery (2014), 133 (3), 571-577CODEN: PRSUAS; ISSN:1529-4242. (Lippincott Williams & Wilkins)
      Background: Capsular contracture is the most common complication following the insertion of breast implants. Within a decade, half of patients will develop capsular contracture, leading to significant morbidity and need for reoperation. There is no preventative treatment available and the recurrence rate remains high. Photochem. tissue passivation is a novel tissue-stabilization technique that results in collagen crosslinking. It can rapidly link collagen fibers in situ, preserving normal tissue architecture. By using this therapy to passivate the collagenous tissues of the implant pocket, the authors hope to prevent the development of pathogenic collagen bundles and subsequent capsule contracture. Methods: Six-cubic centimeter tissue expanders were placed below the panniculus carnosus muscle along the dorsum of New Zealand white rabbits. Fibrin glue was instilled into each implant pocket to induce contracture. Treated pockets received photochem. tissue passivation by coating them with a photosensitizing dye and exposing the area to a 532-nm light. After 8 wk, capsule tissue was harvested for histol. evaluation. Results: Implant capsule thickness is the no. one prognostic factor for contracture development. The authors demonstrated a 52 percent decrease in capsule thickness in the passivated group compared with controls. Photochem. tissue passivation resulted in fewer fibrohistiocytic cells and macrophages and in reduced synovial metaplasia and smooth muscle actin deposition. Conclusions: Photochem. tissue passivation significantly decreased both capsule thickness and smooth muscle actin deposition. It is a promising technique for preventing capsular contracture that can be performed at the time of initial surgery without a significant increase in procedure time.
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    13. 13
      Ludvikova, L.; Fris, P.; Heger, D.; Sebej, P.; Wirz, J.; Klan, P. Photochemistry of rose bengal in water and acetonitrile: a comprehensive kinetic analysis Phys. Chem. Chem. Phys. 2016, 18, 16266– 16273 DOI: 10.1039/C6CP01710J
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      13
      Photochemistry of rose bengal in water and acetonitrile: a comprehensive kinetic analysis
      Ludvikova, Lucie; Fris, Pavel; Heger, Dominik; Sebej, Peter; Wirz, Jakob; Klan, Petr
      Physical Chemistry Chemical Physics (2016), 18 (24), 16266-16273CODEN: PPCPFQ; ISSN:1463-9076. (Royal Society of Chemistry)
      The photophys. and photochem. properties of rose bengal (RB) in degassed aq. and acetonitrile solns. were studied using steady-state and transient absorption spectroscopies. This comprehensive investigation provides detailed information about the kinetics and the optical properties of all intermediates involved: the triplet excited state and the oxidized and reduced forms of RB. A full kinetic description is used to control the concns. of these intermediates by changing the initial exptl. conditions.
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    14. 14
      Neckers, D. C. Rose Bengal J. Photochem. Photobiol. A 1989, 47, 1– 29 DOI: 10.1016/1010-6030(89)85002-6
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      14
      Rose Bengal
      Neckers, D. C.
      Journal of Photochemistry and Photobiology, A: Chemistry (1989), 47 (1), 1-29CODEN: JPPCEJ; ISSN:1010-6030.
      A review with 38 refs. The spectral properties, photochem. reactivity, and photophys. parameters of all of the known derivs. of Rose Bengal, 2,4,5,7-tetraiodo-3',4',5',6'-tetrachlorofluorescein, are reported and compared.
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    15. 15
      Fleming, G. R.; Morris, J. M.; Morrison, R. J. S.; Robinson, G. W. Picosecond fluorescence studies of xanthene dyes J. Am. Chem. Soc. 1977, 99, 4306– 4311 DOI: 10.1021/ja00455a017
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      15
      Picosecond fluorescence studies of xanthene dyes
      Fleming, G. R.; Knight, A. W. E.; Morris, J. M.; Morrison, R. J. S.; Robinson, G. W.
      Journal of the American Chemical Society (1977), 99 (13), 4306-11CODEN: JACSAT; ISSN:0002-7863.
      Subnanosecond lifetime measurements using picosecond pulses from a mode-locked Nd3+-glass laser together with conventional absorption and fluorescence-yield methods are used to study the photophys. of fluorescein, eosin, erythrosin, and rose bengal in aq. and alc. solvents. For each of the dye mols., absorption and fluorescence max. move towards higher energy (blue shift) as the solvent changes from Me2CHOH to H2O. Fluorescence lifetimes and quantum yields decrease with this solvent change and also with increased halogenation of the fluorescein parent, owing to the heavy-atom effect. The variations obsd. in the nonradiative part of the decay rate are attributed to variations in the rate of S1-T1 intersystem crossing. For these particular solvent-solute combinations stabilization energies lie in the order ΔE(T1) < ΔE(S1) < ΔE(S0). This is consistent with both the increased S1-S0 spectral blue shifts and the enhanced intersystem crossing rate, arising from a smaller S1-T1 energy gap, when these dye mols. are placed in a more aq. solvent environment. The use of these dyes as fluorescent probes in biol. important mols. is discussed.
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    16. 16
      Kochevar, I. E.; Redmond, R. W. Photosensitized production of singlet oxygen Methods Enzymol. 2000, 319, 20– 28 DOI: 10.1016/s0076-6879(00)19004-4
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      Photosensitized production of singlet oxygen
      Kochevar, Irene E.; Redmond, Robert W.
      Methods in Enzymology (2000), 319 (), 20-28CODEN: MENZAU; ISSN:0076-6879. (Academic Press)
      A review with 8 refs. Photosensitization is a simple and controllable method for the generation of singlet oxygen in soln. and in cells. Methods are described for detg. the yield of singlet oxygen in soln., for measurement of the rate of reaction between single oxygen and a substrate, and for comparing the effectiveness of singlet oxygen generated by different photosensitizers in cells. These quant. measurements can lead to better understanding of the interaction of singlet oxygen with biomols. (c) 2000 Academic Press.
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    17. 17
      Shen, H. R.; Spikes, J. D.; Kopeckova, P.; Kopecek, J. Photodynamic crosslinking of proteins. II. Photocrosslinking of a model protein-ribonuclease A J. Photochem. Photobiol. B 1996, 35, 213– 219 DOI: 10.1016/S1011-1344(96)07300-9
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      17
      Photodynamic crosslinking of proteins. II. Photocrosslinking of a model protein-ribonuclease A
      Shen, Hui-Rong; Spikes, John D.; Kopeckova, Pavla; Kopecek, Jindrich
      Journal of Photochemistry and Photobiology, B: Biology (1996), 35 (3), 213-219CODEN: JPPBEG; ISSN:1011-1344. (Elsevier)
      Illumination of bovine pancreatic RNase A (RNase A) in soln. in the presence of rose bengal as a photosensitizer resulted in the progressive formation of enzyme dimers, trimers, tetramers and higher oligomers, as measured by gel electrophoresis and size exclusion chromatog. Oxygen was necessary for crosslink formation, and azide inhibition studies indicated that singlet oxygen was involved in the process. Chem. modification of His residues (with di-Et pyrocarbonate) and/or Lys residues (with acetic acid N-hydroxysuccinimide ester) in the enzyme decreased crosslinking, suggesting the participation of these two amino acid residues in the reaction. Met and cystine residues did not appear to be involved. Similar studies have shown that model N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers contg. ε-aminocaproic acid side chains terminating in His or Lys residues are photodynamically crosslinked via His-His or His-Lys interactions. Treatment of crosslinked RNase A and its His, Lys and Lys-His derivs. for 5 min at 97 °C in a dithiothreitol-sodium dodecyl sulfate mixt. efficiently ruptured a major part of the photodynamically formed crosslinks; treatment with the detergent alone had no effect. Similar results were previously obtained with the crosslinked amino acid-contg. HPMA copolymers, suggesting that photodynamic crosslinks involving His-His and His-Lys interaction are chem. the same in RNase A and the copolymer model.
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    18. 18
      Lambert, C. R.; Kochevar, I. E. Electron transfer quenching of the rose bengal triplet state Photochem. Photobiol. 1997, 66, 15– 25 DOI: 10.1111/j.1751-1097.1997.tb03133.x
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      18
      Electron transfer quenching of the rose bengal triplet state
      Lambert, Christopher R.; Kochevar, Irene E.
      Photochemistry and Photobiology (1997), 66 (1), 15-25CODEN: PHCBAP; ISSN:0031-8655. (American Society for Photobiology)
      The potential for electron transfer quenching of rose bengal triplet (3RB2-) to compete with energy transfer quenching by oxygen was evaluated. Rate consts. for oxidative and reductive quenching were measured in buffered aq. soln., acetonitrile and in small unilamellar liposomes using laser flash photolysis. Biol. relevant quenchers were used that varied widely in structure, redn. potential and charge. Radical ion yields (φi) were measured by monitoring the absorption of the rose bengal semireduced (RB·3-) and semioxidized (RB·-) radicals. The results in soln. were analyzed as a function of the free energy for electron transfer (ΔG) calcd. using the Weller equation including electrostatic terms. Exothermic oxidative quenching was about 10-fold faster than exothermic reductive quenching in aq. soln. The quenching rate consts. decreased as ΔG approached zero in both aq. and acetonitrile soln. Exceptions to these generalizations were obsd. that could be rationalized by specific steric or electrostatic effects or by a change in mechanism. The results suggest that electron transfer reactions with some potential quenchers in cells could compete with formation of singlet oxygen [O2(1Δg)]. Values of φi were generally greater for reductive quenching and, for oxidative quenching, greater in acetonitrile than in buffer. Electron transfer quenching of 3RB2- in liposomes, below the phase transition temp. was slower than in soln. for both lipid-sol. and water-sol. quenchers indicating that these reactions may not compete with formation of (O21Δg) during cell photosensitization.
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    19. 19
      Zakrzewski, A.; Neckers, D. C. Bleaching products of rose bengal under reducing conditions Tetrahedron 1987, 43, 4507– 4512 DOI: 10.1016/S0040-4020(01)86891-5
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      Bleaching products of Rose Bengal under reducing conditions
      Zakrzewski, Andrzej; Neckers, D. C.
      Tetrahedron (1987), 43 (20), 4507-12CODEN: TETRAB; ISSN:0040-4020.
      The bleaching behavior of Rose Bengal under reducing conditions was elucidated by detg. the products of chem. and photochem. redn. of Rose Bengal.
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      Oster, G.; Oster, G. K.; Karg, G. Extremely long-lived intermediates in photochemical reactions of dyes in non-visous media J. Phys. Chem. 1962, 66, 2514– 2517 DOI: 10.1021/j100818a045
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      Luttrull, D. K.; Valdes-Aguilera, O.; Linden, S. M.; Paczkowski, J.; Neckers, D. C. Rose Bengal aggregation in rationally synthesized dimeric systems Photochem. Photobiol. 1988, 47, 551– 557 DOI: 10.1111/j.1751-1097.1988.tb08843.x
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      Simpson, M. J.; Poblete, H.; Griffith, M.; Alarcon, E. I.; Scaiano, J. C. Impact of dye-protein interaction and silver nanoparticles on rose bengal photophysical behavior and protein photocrosslinking Photochem. Photobiol. 2013, 89, 1433– 1441 DOI: 10.1111/php.12119
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      Valdes-Aguilera, O.; Neckers, D. C. Aggregation phenomena in xanthene dyes Acc. Chem. Res. 1989, 22, 171– 177 DOI: 10.1021/ar00161a002
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      Aggregation phenomena in xanthene dyes
      Valdes-Aguilera, Oscar; Neckers, D. C.
      Accounts of Chemical Research (1989), 22 (5), 171-7CODEN: ACHRE4; ISSN:0001-4842.
      A crit. review with 63 refs. on aggregation of xanthene dyes, principally rhodamines and fluoresceins. The author's work on Rose Bengal is considered in detail.
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      Xu, D.; Neckers, D. C. Aggregation of rose bengal molecules in solution J. Photochem. Photobiol. A 1987, 40, 361– 370 DOI: 10.1016/1010-6030(87)85013-X
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      24
      Aggregation of Rose Bengal molecules in solution
      Xu, Danian; Neckers, D. C.
      Journal of Photochemistry and Photobiology, A: Chemistry (1987), 40 (2-3), 361-70CODEN: JPPCEJ; ISSN:1010-6030.
      Absorption, emission, and excitation spectral data support the hypothesis that Rose Bengal forms H-type aggregates in water and in polar, protic solvents.
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    25. 25
      Alarcón, E.; Edwards, A. M.; Aspee, A.; Borsarelli, C. D.; Lissi, E. A. Photophysics and photochemistry of rose bengal bound to human serum albumin Photochem. Photobiol. Sci. 2009, 8, 933– 943 DOI: 10.1039/b901056d
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      25
      Photophysics and photochemistry of rose bengal bound to human serum albumin
      Alarcon, Emilio; Edwards, Ana Maria; Aspee, Alexis; Borsarelli, Claudio D.; Lissi, Eduardo A.
      Photochemical & Photobiological Sciences (2009), 8 (7), 933-943CODEN: PPSHCB; ISSN:1474-905X. (Royal Society of Chemistry)
      Rose bengal (RB) readily binds to human serum albumin (HSA). At low RB concns., 90% of the dye is assocd. to the protein (5 μM). This assocn. takes place in specific binding sites I and/or II. At higher RB concns., unspecific binding takes place with up to 10 RB mols. bound per protein mol. The behavior of excited RB mols. bound to HSA is widely different to that obsd. in aq. soln. Furthermore, the data also show that the behavior of bound RB mols. changes with the av. no. of dye mols. per protein (n). In particular, when n is large, the fluorescence yield is significantly reduced and no measurable long-lived triples and free singlet oxygen formation from bound dyes is detected. These results are related to self-quenching of the singlet and, most likely, excited triplets. All results point to the relevance of intra-protein generated singlet oxygen. However, when the dye is bound to the protein, at low oxygen concns. such as those prevailing in vivo, trapping by oxygen of the triplet becomes inefficient and type I processes could contribute to the obsd. photoprocesses.
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    26. 26
      Ni, T.; Senthil-Kumar, P.; Dubbin, K.; Aznar-Cervantes, S. D.; Datta, N.; Randolph, M. A.; Cenis, J. L.; Rutledge, G. C.; Kochevar, I. E.; Redmond, R. W. A photoactivated nanofiber graft material for augmented Achilles tendon repair Lasers Surg. Med. 2012, 44, 645– 652 DOI: 10.1002/lsm.22066
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      A photoactivated nanofiber graft material for augmented Achilles tendon repair
      Ni Tao; Senthil-Kumar Prabhu; Dubbin Karen; Aznar-Cervantes Salvador D; Datta Neha; Randolph Mark A; Cenis Jose L; Rutledge Gregory C; Kochevar Irene E; Redmond Robert W
      Lasers in surgery and medicine (2012), 44 (8), 645-52 ISSN:.
      BACKGROUND AND OBJECTIVE: Suture repair of Achilles tendon rupture can cause infection, inflammation and scarring, while prolonged immobilization promotes adhesions to surrounding tissues and joint stiffness. Early mobilization can reduce complications provided the repair is strong enough to resist re-rupture. We have developed a biocompatible, photoactivated tendon wrap from electrospun silk (ES) to provide additional strength to the repair that could permit early mobilization, and act as a barrier to adhesion formation. STUDY DESIGN/MATERIAL AND METHODS: ES nanofiber mats were prepared by electrospinning. New Zealand white rabbits underwent surgical transection of the Achilles tendon and repair by: (a) SR: standard Kessler suture + epitendinous suture (5-0 vicryl). (b) ES/PTB: a single stay suture and a section of ES mat, stained with 0.1% Rose Bengal (RB), wrapped around the tendon and bonded with 532 nm light (0.3 W/cm(2) , 125 J/cm(2) ). (c) SR + ES/PTB: a combination of (a) and (b). Gross appearance, extent of adhesion formation and biomechanical properties of the repaired tendon were evaluated at Days 7, 14, or 28 post-operatively (n = 8 per group at each time point). RESULTS: Ultimate stress (US) and Young's modulus (E) in the SR group were not significantly different from the ES/PTB group at Days 7 (US, P = 0.85; E, P = 1), 14 (US, P = 0.054; E, P = 1), and 28 (US, P = 0.198; E, P = 0.12) post-operatively. Adhesions were considerably greater in the SR group compared to the ES/PTB group at Days 7 (P = 0.002), 14 (P < 0.0001), and 28 (P < 0.0001). The combination approach of SR + ES/PTB gave the best outcomes in terms of E at 7 (P < 0.016) and 14 days (P < 0.016) and reduced adhesions compared to SR at 7 (P < 0.0001) and 14 days (P < 0.0001), the latter suggesting a barrier function for the photobonded ES wrap. CONCLUSION: Photochemical sealing of a ES mat around the tendon repair site provides considerable benefit in Achilles tendon repair. Lasers Surg. Med. 44: 645-652, 2012. © 2012 Wiley Periodicals, Inc.
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    27. 27
      Stetefeld, J.; Frank, S.; Jenny, M.; Schulthess, T.; Kammerer, R. A.; Boudko, S.; Landwehr, R.; Okuyama, K.; Engel, J. Collagen stabilization at atomic level: crystal structure of designed (GlyProPro)10foldon Structure 2003, 11, 339– 346 DOI: 10.1016/S0969-2126(03)00025-X
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      Collagen Stabilization at Atomic Level Crystal Structure of Designed (GlyProPro)10foldon
      Stetefeld, Jorg; Frank, Sabine; Jenny, Margrit; Schulthess, Therese; Kammerer, Richard A.; Boudko, Sergei; Landwehr, Ruth; Okuyama, Kenji; Engel, Jurgen
      Structure (Cambridge, MA, United States) (2003), 11 (3), 339-346CODEN: STRUE6; ISSN:0969-2126. (Cell Press)
      In a designed fusion protein the trimeric domain foldon from bacteriophage T4 fibritin was connected to the C terminus of the collagen model peptide (GlyProPro)10 by a short Gly-Ser linker to facilitate formation of the three-stranded collagen triple helix. Crystal structure anal. at 2.6 A resoln. revealed conformational changes within the interface of both domains compared with the structure of the isolated mols. A striking feature is an angle of 62.5° between the symmetry axis of the foldon trimer and the axis of the triple helix. The melting temp. of (GlyProPro)10 in the designed fusion protein (GlyProPro)10foldon is higher than that of isolated (GlyProPro)10, which suggests an entropic stabilization compensating for the destabilization at the interface.
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    28. 28
      Mirenda, M.; Dicelio, L. E.; San Roman, E. Effect of molecular interactions on the photophysics of Rose Bengal in polyelectrolyte solutions and self-assembled thin films J. Phys. Chem. B 2008, 112, 12201– 12207 DOI: 10.1021/jp803892g
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      Effect of molecular interactions on the photophysics of Rose Bengal in polyelectrolyte solutions and self-assembled thin films
      Mirenda, Martin; Dicelio, Lelia E.; San Roman, Enrique
      Journal of Physical Chemistry B (2008), 112 (39), 12201-12207CODEN: JPCBFK; ISSN:1520-6106. (American Chemical Society)
      Aq. solns. and layer-by-layer self-assembled thin films contg. Rose Bengal and poly(diallyldimethylammonium chloride) are studied with the aim of understanding the interactions controlling their structures and the photophysics of the dye in both media. A detailed spectroscopic and theor. anal. shows that hydrophobic interactions among dye mols. contribute to the coiling of the polyelectrolyte chain in soln. at low polyelectrolyte/dye (P/D) ratios, whereas extensive aggregation of the dye takes place even at ratios as high as 104 (expressed in monomeric units). A polyelectrolyte elongated form prevails in self-assembled thin films, providing an environment that reduces hydrophobic interactions and lowers the aggregation tendency. Self-assembled films with a roughly estd. overall dye concn. around 1 M at a P/D ratio in the order of seven are fluorescent and photogenerate singlet mol. oxygen. This contrasts with the behavior of polyelectrolyte solns., which are almost nonfluorescent and do not evidence triplet state generation at the same P/D ratio.
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      Rodríguez, H. B.; Lagorio, M. G.; San Roman, E. Rose Bengal adsorbed on microgranular cellulose: evidence on fluorescent dimers Photochem. Photobiol. Sci. 2004, 3, 674– 680 DOI: 10.1039/B402484B
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      Rose Bengal adsorbed on microgranular cellulose: evidence on fluorescent dimers
      Rodriguez, Hernan B.; Lagorio, M. Gabriela; San Roman, Enrique
      Photochemical & Photobiological Sciences (2004), 3 (7), 674-680CODEN: PPSHCB; ISSN:1474-905X. (Royal Society of Chemistry)
      Rose Bengal adsorbed on microgranular cellulose was studied in the solid phase by total and diffuse reflectance and steady-state emission spectroscopy. A simple self-assocn. monomer-dimer equil. fitted reflectance data up to dye loadings of 4 × 10-7 mol (g cellulose)-1 and allowed calcn. of monomer and dimer spectra. Further increase of dye loading resulted in the formation of higher aggregates. Obsd. emission and excitation spectra and quantum yields were cor. for reabsorption and reemission of luminescence, using a previously developed model, within the assumption that only monomers are luminescent. An apparent increase of fluorescence quantum yield with dye loading was found, which was attributed to the occurrence of dimer fluorescence. Extension of the model to two luminescent species (i.e. monomer and dimer) yielded const. fluorescence quantum yields for the monomer, ΦM = 0.120 ± 0.004, and for the dimer, ΦD = 0.070 ± 0.006. The monomer quantum yield is close to the value found for the same dye in basic ethanol. The presence of fluorescent dimers and calcd. quantum yields are supported by anal. of the excitation spectra and other exptl. evidence. The possible occurrence of non-radiative energy transfer and the effect of surface charge on the properties of the dimer are analyzed.
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    30. 30
      Lissi, E. A.; Encinas, M. V.; Lemp, E.; Rubio, M. A. Singlet oxygen O2(1.DELTA.g) bimolecular processes. Solvent and compartmentalization effects Chem. Rev. 1993, 93, 699– 723 DOI: 10.1021/cr00018a004
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      Singlet oxygen O2(1Δg) bimolecular processes. Solvent and compartmentalization effects
      Lissi, E. A.; Encinas, M. V.; Lemp, E.; Rubio, M. A.
      Chemical Reviews (Washington, DC, United States) (1993), 93 (2), 699-723CODEN: CHREAY; ISSN:0009-2665.
      A review with >401 refs. including (1) deactivation dominated by energy transfer, (2) dyes and sensitizers, (3) inorg. anions, (4) N-contg. compds., (5) S-contg. compds., (6) unsatd. compds., and (7) microheterogeneous systems.
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      Alarcón, E.; Edwards, A. M.; Aspee, A.; Moran, F. E.; Borsarelli, C. D.; Lissi, E. A.; Gonzalez-Nilo, D.; Poblete, H.; Scaiano, J. C. Photophysics and photochemistry of dyes bound to human serum albumin are determined by the dye localization Photochem. Photobiol. Sci. 2010, 9, 93– 102 DOI: 10.1039/B9PP00091G
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      Photophysics and photochemistry of dyes bound to human serum albumin are determined by the dye localization
      Alarcon, Emilio; Edwards, Ana Maria; Aspee, Alexis; Moran, Faustino E.; Borsarelli, Claudio D.; Lissi, Eduardo A.; Gonzalez-Nilo, Danilo; Poblete, Horacio; Scaiano, J. C.
      Photochemical & Photobiological Sciences (2010), 9 (1), 93-102CODEN: PPSHCB; ISSN:1474-905X. (Royal Society of Chemistry)
      The photophysics and photochem. of rose bengal (RB) and methylene blue (MB) bound to human serum albumin (HSA) have been investigated under a variety of exptl. conditions. Distribution of the dyes between the external solvent and the protein has been estd. by phys. sepn. and fluorescence measurements. The main localization of protein-bound dye mols. was estd. by the intrinsic fluorescence quenching, displacement of fluorescent probes bound to specific protein sites, and by docking modeling. All the data indicate that, at low occupation nos., RB binds strongly to the HSA site I, while MB localizes predominantly in the protein binding site II. This different localization explains the obsd. differences in the dyes' photochem. behavior. In particular, the environment provided by site I is less polar and considerably less accessible to oxygen. The localization of RB in site I also leads to an efficient quenching of the intrinsic protein fluorescence (ascribed to the nearby Trp residue) and the generation of intra-protein singlet oxygen, whose behavior is different to that obsd. in the external solvent or when it is generated by bound MB.
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      Mills, A.; Lawrence, C.; Douglas, P. Photoreduction of Water sensitised by Rose Bengal J. Chem. Soc., Faraday Trans. 2 1986, 82, 2291– 2303 DOI: 10.1039/f29868202291
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      Photoreduction of water sensitized by Rose Bengal
      Mills, Andrew; Lawrence, Carl; Douglas, Peter
      Journal of the Chemical Society, Faraday Transactions 2: Molecular and Chemical Physics (1986), 82 (12), 2291-303CODEN: JCFTBS; ISSN:0300-9238.
      Rose Bengal was used to sensitize the photoredn. of H2O in aq. EtOH soln. (5% EtOH vol./vol.; ph 4.4) via both a reductive and an oxidative quenching mechanism, using EDTA and methylviologen, resp., as quenchers of its triplet state. In the presence of EDTA (which acts as both triplet quencher and sacrificial electron donor) the photoredn. of H2O sensitized by Rose Bengal was inefficient for a no. of reasons, including a low triplet quenching rate const. (8 × 103 dm3 mol-1 s-1) and a rapid disproportionation reaction involving the protonated semi-reduced dye radicals. In the presence of methylviologen (triplet quencher) and EDTA (sacrificial electron donor) the photoredn. of H2O sensitized by Rose Bengal was inefficient due to a low cage-escape yield (.vphi. ≈ 5 × 10-2) following the primary electron-transfer step, a fast back reaction (k ≥ 1 × 108 dm3 mol-1 s-1) and formation of a complex between the dye and methylviologen (K = 6400 ± 300 cm3 mol-). The complexed form of Rose Bengal appeared able to photosensitize, inefficiently, the photoredn. of methylviologen in the presence of EDTA, without exhibiting problems of dye fade.
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    33. 33
      Pupkaite, J.; Ahumada, M.; McLaughlin, S.; Temkit, M.; Alaziz, S.; Seymour, R.; Ruel, M.; Kochevar, I.; Griffith, M.; Suuronen, E. J.; Alarcon, E. I. Collagen-Based Photoactive Agent for Tissue Bonding ACS Appl. Mater. Interfaces 2017, 9, 9265– 9270 DOI: 10.1021/acsami.7b01984
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      Collagen-Based Photoactive Agent for Tissue Bonding
      Pupkaite, Justina; Ahumada, Manuel; Mclaughlin, Sarah; Temkit, Maha; Alaziz, Sura; Seymour, Richard; Ruel, Marc; Kochevar, Irene; Griffith, May; Suuronen, Erik J.; Alarcon, Emilio I.
      ACS Applied Materials & Interfaces (2017), 9 (11), 9265-9270CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)
      Using a combination of methacrylated collagen and the photosensitizer rose Bengal, a new light-activated biomimetic material for tissue sutureless bonding was developed. This formulation was crosslinked using green light. In vivo tests in mice demonstrate the suitability of the material for sutureless wound closure.
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      Henderson, B. W.; Busch, T. M.; Vaughan, L. A.; Frawley, N. P.; Babich, D.; Sosa, T. A.; Zollo, J. D.; Dee, A. S.; Cooper, M. T.; Bellnier, D. A.; Greco, W. R.; Oseroff, A. R. Photofrin photodynamic therapy can significantly deplete or preserve oxygenation in human basal cell carcinomas during treatment, depending on fluence rate Cancer Res. 2000, 60, 525– 529
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      Photofrin photodynamic therapy can significantly deplete or preserve oxygenation in human basal cell carcinomas during treatment, depending on fluence rate
      Henderson, Barbara W.; Busch, Theresa M.; Vaughan, Lurine A.; Frawley, Noreen P.; Babich, Debra; Sosa, Tara A.; Zollo, Joseph D.; Dee, Anthony S.; Cooper, Michele T.; Bellnier, David A.; Greco, William R.; Oseroff, Allan R.
      Cancer Research (2000), 60 (3), 525-529CODEN: CNREA8; ISSN:0008-5472. (AACR Subscription Office)
      At high fluence rates in animal models, photodynamic therapy (PDT) can photochem. deplete ambient tumor oxygen through the generation of singlet oxygen, causing acute hypoxia and limiting treatment effectiveness. We report that std. clin. treatment conditions (1 mg/kg Photofrin, light at 630 nm and 150 mW/cm2), which are highly effective for treating human basal cell carcinomas, significantly diminished tumor oxygen levels during initial light delivery in a majority of carcinomas. Oxygen depletion could be found during at least 40% of the total light dose, but tumors appeared well oxygenated toward the end of treatment. In contrast, initial light delivery at a lower fluence rate of 30 mW/cm2 increased tumor oxygenation in a majority of carcinomas. Laser treatment caused an intensity- and treatment time-dependent increase in tumor temp. The data suggest that high fluence rate treatment, although effective, may be inefficient.
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      Ravichandran, R.; Islam, M. M.; Alarcon, E. I.; Samanta, A.; Wang, S.; Lundstrom, P.; Hilborn, J.; Griffith, M.; Phopase, J. Functionalised type-I collagen as a hydrogel building block for bio-orthogonal tissue engineering applications J. Mater. Chem. B. 2016, 4, 318– 326 DOI: 10.1039/C5TB02035B
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      Functionalised type-I collagen as a hydrogel building block for bio-orthogonal tissue engineering applications
      Ravichandran, R.; Islam, M. M.; Alarcon, E. I.; Samanta, A.; Wang, S.; Lundstroem, P.; Hilborn, J.; Griffith, M.; Phopase, J.
      Journal of Materials Chemistry B: Materials for Biology and Medicine (2016), 4 (2), 318-326CODEN: JMCBDV; ISSN:2050-7518. (Royal Society of Chemistry)
      In this study, we derivatized type I collagen without altering its triple helical conformation to allow for facile hydrogel formation via the Michael addn. of thiols to methacrylates without the addn. of other crosslinking agents. This method provides the flexibility needed for the fabrication of injectable hydrogels or pre-fabricated implantable scaffolds, using the same components by tuning the modulus from Pa to kPa. Enzymic degradability of the hydrogels can also be easily fine-tuned by variation of the ratio and the type of the crosslinking component. The structural morphol. reveals a lamellar structure mimicking native collagen fibrils. The versatility of this material is demonstrated by its use as a pre-fabricated substrate for culturing human corneal epithelial cells and as an injectable hydrogel for 3-D encapsulation of cardiac progenitor cells.
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      Biasini, M.; Bienert, S.; Waterhouse, A.; Arnold, K.; Studer, G.; Schmidt, T.; Kiefer, F.; Gallo Cassarino, T.; Bertoni, M.; Bordoli, L.; Schwede, T. SWISS-MODEL: modelling protein tertiary and quaternary structure using evolutionary information Nucleic Acids Res. 2014, 42, W252– W258 DOI: 10.1093/nar/gku340
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      SWISS-MODEL: modelling protein tertiary and quaternary structure using evolutionary information
      Biasini, Marco; Bienert, Stefan; Waterhouse, Andrew; Arnold, Konstantin; Studer, Gabriel; Schmidt, Tobias; Kiefer, Florian; Cassarino, Tiziano Gallo; Bertoni, Martino; Bordoli, Lorenza; Schwede, Torsten
      Nucleic Acids Research (2014), 42 (W1), W252-W258CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)
      Protein structure homol. modeling has become a routine technique to generate 3D models for proteins when exptl. structures are not available. Fully automated servers such as SWISS-MODEL with user-friendly web interfaces generate reliable models without the need for complex software packages or downloading large databases. Here, we describe the latest version of the SWISS-MODEL expert system for protein structure modeling. The SWISS-MODEL template library provides annotation of quaternary structure and essential ligands and co-factors to allow for building of complete structural models, including their oligomeric structure. The improved SWISS-MODEL pipeline makes extensive use of model quality estn. for selection of the most suitable templates and provides ests. of the expected accuracy of the resulting models. The accuracy of the models generated by SWISS-MODEL is continuously evaluated by the CAMEO system. The new web site allows users to interactively search for templates, cluster them by sequence similarity, structurally compare alternative templates and select the ones to be used for model building. In cases where multiple alternative template structures are available for a protein of interest, a user-guided template selection step allows building models in different functional states. SWISS-MODEL is available at http://swissmodel.expasy.org/.
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      Vanommeslaeghe, K.; Hatcher, E.; Acharya, C.; Kundu, S.; Zhong, S.; Shim, J.; Darian, E.; Guvench, O.; Lopes, P.; Vorobyov, I.; Mackerell, A. D., Jr. CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields J. Comput. Chem. 2010, 31, 671– 690 DOI: 10.1002/jcc.21367
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      CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields
      Vanommeslaeghe, K.; Hatcher, E.; Acharya, C.; Kundu, S.; Zhong, S.; Shim, J.; Darian, E.; Guvench, O.; Lopes, P.; Vorobyov, I.; Mackerell, A. D., Jr.
      Journal of Computational Chemistry (2010), 31 (4), 671-690CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)
      The widely used CHARMM additive all-atom force field includes parameters for proteins, nucleic acids, lipids, and carbohydrates. In the present article, an extension of the CHARMM force field to drug-like mols. is presented. The resulting CHARMM General Force Field (CGenFF) covers a wide range of chem. groups present in biomols. and drug-like mols., including a large no. of heterocyclic scaffolds. The parametrization philosophy behind the force field focuses on quality at the expense of transferability, with the implementation concg. on an extensible force field. Statistics related to the quality of the parametrization with a focus on exptl. validation are presented. Addnl., the parametrization procedure, described fully in the present article in the context of the model systems, pyrrolidine, and 3-phenoxymethyl-pyrrolidine will allow users to readily extend the force field to chem. groups that are not explicitly covered in the force field as well as add functional groups to and link together mols. already available in the force field. CGenFF thus makes it possible to perform "all-CHARMM" simulations on drug-target interactions thereby extending the utility of CHARMM force fields to medicinally relevant systems. © 2009 Wiley Periodicals, Inc.J Comput Chem, 2010.
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      Vanommeslaeghe, K.; MacKerell, A. D., Jr. Automation of the CHARMM General Force Field (CGenFF) I: bond perception and atom typing J. Chem. Inf. Model. 2012, 52, 3144– 3154 DOI: 10.1021/ci300363c
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      Automation of the CHARMM General Force Field (CGenFF) I: Bond Perception and Atom Typing
      Vanommeslaeghe, K.; MacKerell, A. D.
      Journal of Chemical Information and Modeling (2012), 52 (12), 3144-3154CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)
      Mol. mechanics force fields are widely used in computer-aided drug design for the study of drug-like mols. alone or interacting with biol. systems. In simulations involving biol. macromols., the biol. part is typically represented by a specialized biomol. force field, while the drug is represented by a matching general (org.) force field. In order to apply these general force fields to an arbitrary drug-like mol., functionality for assignment of atom types, parameters, and charges is required. In the present article, which is part I of a series of two, we present the algorithms for bond perception and atom typing for the CHARMM General Force Field (CGenFF). The CGenFF atom typer first assocs. attributes to the atoms and bonds in a mol., such as valence, bond order, and ring membership among others. Of note are a no. of features that are specifically required for CGenFF. This information is then used by the atom typing routine to assign CGenFF atom types based on a programmable decision tree. This allows for straight-forward implementation of CGenFF's complicated atom typing rules and for equally straight-forward updating of the atom typing scheme as the force field grows. The presented atom typer was validated by assigning correct atom types on 477 model compds. including in the training set as well as 126 test-set mols. that were constructed to specifically verify its different components. The program may be utilized via an online implementation at https://www.paramchem.org/.
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      Vanommeslaeghe, K.; Raman, E. P.; MacKerell, A. D., Jr. Automation of the CHARMM General Force Field (CGenFF) II: assignment of bonded parameters and partial atomic charges J. Chem. Inf. Model. 2012, 52, 3155– 3168 DOI: 10.1021/ci3003649
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      Automation of the CHARMM General Force Field (CGenFF) II: Assignment of Bonded Parameters and Partial Atomic Charges
      Vanommeslaeghe, K.; Raman, E. Prabhu; MacKerell, A. D.
      Journal of Chemical Information and Modeling (2012), 52 (12), 3155-3168CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)
      Mol. mechanics force fields are widely used in computer-aided drug design for the study of drug candidates interacting with biol. systems. In these simulations, the biol. part is typically represented by a specialized biomol. force field, while the drug is represented by a matching general (org.) force field. In order to apply these general force fields to an arbitrary drug-like mol., functionality for assignment of atom types, parameters, and partial at. charges is required. In the present article, algorithms for the assignment of parameters and charges for the CHARMM General Force Field (CGenFF) are presented. These algorithms rely on the existing parameters and charges that were detd. as part of the parametrization of the force field. Bonded parameters are assigned based on the similarity between the atom types that define said parameters, while charges are detd. using an extended bond-charge increment scheme. Charge increments were optimized to reproduce the charges on model compds. that were part of the parametrization of the force field. Case studies are presented to clarify the functioning of the algorithms and the significance of their output data.
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    40. 40
      Best, R. B.; Zhu, X.; Shim, J.; Lopes, P. E.; Mittal, J.; Feig, M.; Mackerell, A. D., Jr. Optimization of the additive CHARMM all-atom protein force field targeting improved sampling of the backbone phi, psi and side-chain chi(1) and chi(2) dihedral angles J. Chem. Theory. Comput. 2012, 8, 3257– 3273 DOI: 10.1021/ct300400x
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      Optimization of the Additive CHARMM All-Atom Protein Force Field Targeting Improved Sampling of the Backbone .vphi., ψ and Side-Chain χ1 and χ2 Dihedral Angles
      Best, Robert B.; Zhu, Xiao; Shim, Jihyun; Lopes, Pedro E. M.; Mittal, Jeetain; Feig, Michael; MacKerell, Alexander D.
      Journal of Chemical Theory and Computation (2012), 8 (9), 3257-3273CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)
      While the quality of the current CHARMM22/CMAP additive force field for proteins has been demonstrated in a large no. of applications, limitations in the model with respect to the equil. between the sampling of helical and extended conformations in folding simulations have been noted. To overcome this, as well as make other improvements in the model, we present a combination of refinements that should result in enhanced accuracy in simulations of proteins. The common (non-Gly, -Pro) backbone CMAP potential has been refined against exptl. soln. NMR data for weakly structured peptides, resulting in a rebalancing of the energies of the α-helix and extended regions of the Ramachandran map, correcting the α-helical bias of CHARMM22/CMAP. The Gly and Pro CMAPs have been refitted to more accurate quantum-mech. energy surfaces. Side-chain torsion parameters have been optimized by fitting to backbone-dependent quantum-mech. energy surfaces, followed by addnl. empirical optimization targeting NMR scalar couplings for unfolded proteins. A comprehensive validation of the revised force field was then performed against a collection of exptl. data: (i) comparison of simulations of eight proteins in their crystal environments with crystal structures; (ii) comparison with backbone scalar couplings for weakly structured peptides; (iii) comparison with NMR residual dipolar couplings and scalar couplings for both backbone and side-chains in folded proteins; (iv) equil. folding of mini-proteins. The results indicate that the revised CHARMM 36 parameters represent an improved model for modeling and simulation studies of proteins, including studies of protein folding, assembly, and functionally relevant conformational changes.
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      Phillips, J. C.; Braun, R.; Wang, W.; Gumbart, J.; Tajkhorshid, E.; Villa, E.; Chipot, C.; Skeel, R. D.; Kale, L.; Schulten, K. Scalable molecular dynamics with NAMD J. Comput. Chem. 2005, 26, 1781– 1802 DOI: 10.1002/jcc.20289
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      Scalable molecular dynamics with NAMD
      Phillips, James C.; Braun, Rosemary; Wang, Wei; Gumbart, James; Tajkhorshid, Emad; Villa, Elizabeth; Chipot, Christophe; Skeel, Robert D.; Kale, Laxmikant; Schulten, Klaus
      Journal of Computational Chemistry (2005), 26 (16), 1781-1802CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)
      NAMD is a parallel mol. dynamics code designed for high-performance simulation of large biomol. systems. NAMD scales to hundreds of processors on high-end parallel platforms, as well as tens of processors on low-cost commodity clusters, and also runs on individual desktop and laptop computers. NAMD works with AMBER and CHARMM potential functions, parameters, and file formats. This article, directed to novices as well as experts, first introduces concepts and methods used in the NAMD program, describing the classical mol. dynamics force field, equations of motion, and integration methods along with the efficient electrostatics evaluation algorithms employed and temp. and pressure controls used. Features for steering the simulation across barriers and for calcg. both alchem. and conformational free energy differences are presented. The motivations for and a roadmap to the internal design of NAMD, implemented in C++ and based on Charm++ parallel objects, are outlined. The factors affecting the serial and parallel performance of a simulation are discussed. Finally, typical NAMD use is illustrated with representative applications to a small, a medium, and a large biomol. system, highlighting particular features of NAMD, for example, the Tcl scripting language. The article also provides a list of the key features of NAMD and discusses the benefits of combining NAMD with the mol. graphics/sequence anal. software VMD and the grid computing/collab. software BioCoRE. NAMD is distributed free of charge with source code at www.ks.uiuc.edu.
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      MacKerell, A. D.; Bashford, D.; Bellott, M.; Dunbrack, R. L.; Evanseck, J. D.; Field, M. J.; Fischer, S.; Gao, J.; Guo, H.; Ha, S.; Joseph-McCarthy, D.; Kuchnir, L.; Kuczera, K.; Lau, F. T.; Mattos, C.; Michnick, S.; Ngo, T.; Nguyen, D. T.; Prodhom, B.; Reiher, W. E.; Roux, B.; Schlenkrich, M.; Smith, J. C.; Stote, R.; Straub, J.; Watanabe, M.; Wiorkiewicz-Kuczera, J.; Yin, D.; Karplus, M. All-atom empirical potential for molecular modeling and dynamics studies of proteins J. Phys. Chem. B 1998, 102, 3586– 3616 DOI: 10.1021/jp973084f
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      All-Atom Empirical Potential for Molecular Modeling and Dynamics Studies of Proteins
      MacKerell, A. D., Jr.; Bashford, D.; Bellott, M.; Dunbrack, R. L.; Evanseck, J. D.; Field, M. J.; Fischer, S.; Gao, J.; Guo, H.; Ha, S.; Joseph-McCarthy, D.; Kuchnir, L.; Kuczera, K.; Lau, F. T. K.; Mattos, C.; Michnick, S.; Ngo, T.; Nguyen, D. T.; Prodhom, B.; Reiher, W. E., III; Roux, B.; Schlenkrich, M.; Smith, J. C.; Stote, R.; Straub, J.; Watanabe, M.; Wiorkiewicz-Kuczera, J.; Yin, D.; Karplus, M.
      Journal of Physical Chemistry B (1998), 102 (18), 3586-3616CODEN: JPCBFK; ISSN:1089-5647. (American Chemical Society)
      New protein parameters are reported for the all-atom empirical energy function in the CHARMM program. The parameter evaluation was based on a self-consistent approach designed to achieve a balance between the internal (bonding) and interaction (nonbonding) terms of the force field and among the solvent-solvent, solvent-solute, and solute-solute interactions. Optimization of the internal parameters used exptl. gas-phase geometries, vibrational spectra, and torsional energy surfaces supplemented with ab initio results. The peptide backbone bonding parameters were optimized with respect to data for N-methylacetamide and the alanine dipeptide. The interaction parameters, particularly the at. charges, were detd. by fitting ab initio interaction energies and geometries of complexes between water and model compds. that represented the backbone and the various side chains. In addn., dipole moments, exptl. heats and free energies of vaporization, solvation and sublimation, mol. vols., and crystal pressures and structures were used in the optimization. The resulting protein parameters were tested by applying them to noncyclic tripeptide crystals, cyclic peptide crystals, and the proteins crambin, bovine pancreatic trypsin inhibitor, and carbonmonoxy myoglobin in vacuo and in a crystal. A detailed anal. of the relationship between the alanine dipeptide potential energy surface and calcd. protein φ, χ angles was made and used in optimizing the peptide group torsional parameters. The results demonstrate that use of ab initio structural and energetic data by themselves are not sufficient to obtain an adequate backbone representation for peptides and proteins in soln. and in crystals. Extensive comparisons between mol. dynamics simulation and exptl. data for polypeptides and proteins were performed for both structural and dynamic properties. Calcd. data from energy minimization and dynamics simulations for crystals demonstrate that the latter are needed to obtain meaningful comparisons with exptl. crystal structures. The presented parameters, in combination with the previously published CHARMM all-atom parameters for nucleic acids and lipids, provide a consistent set for condensed-phase simulations of a wide variety of mols. of biol. interest.
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      A new method for performing mol. dynamics simulations under const. pressure is presented. In the method, which is based on the extended system formalism introduced by Andersen, the deterministic equations of motion for the piston degree of freedom are replaced by a Langevin equation; a suitable choice of collision frequency then eliminates the unphys. "ringing" of the vol. assocd. with the piston mass. In this way it is similar to the "weak coupling algorithm" developed by Berendsen and co-workers to perform mol. dynamics simulation without piston mass effects. It is shown, however, that the weak coupling algorithm induces artifacts into the simulation which can be quite severe for inhomogeneous systems such as aq. biopolymers or liq./liq. interfaces.
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      An N·log(N) method for evaluating electrostatic energies and forces of large periodic systems is presented. The method is based on interpolation of the reciprocal space Ewald sums and evaluation of the resulting convolution using fast Fourier transforms. Timings and accuracies are presented for three large cryst. ionic systems.
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      An algorithm, called RATTLE, for integrating the equations of motion in mol. dynamics calcns. for mol. models with internal constraints is presented. RATTLE calcs. the positions and velocities at the next time from the positions and velocities at the present time step, without requiring information about the earlier history. It is based on the Verlet algorithm and retains the simplicity of using Cartesian coordinates for each of the atoms to describe the configuration of a mol. with internal constraints. RATTLE guarantees that the coordinates and velocities of the atoms in a mol. satisfy the internal constraints at each time step.
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      Hopkins, C. W.; Le Grand, S.; Walker, R. C.; Roitberg, A. E. Long-Time-Step Molecular Dynamics through Hydrogen Mass Repartitioning J. Chem. Theory Comput. 2015, 11, 1864– 1874 DOI: 10.1021/ct5010406
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      Previous studies have shown that the method of hydrogen mass repartitioning (HMR) is a potentially useful tool for accelerating mol. dynamics (MD) simulations. By repartitioning the mass of heavy atoms into the bonded hydrogen atoms, it is possible to slow the highest-frequency motions of the macromol. under study, thus allowing the time step of the simulation to be increased by up to a factor of 2. In this communication, we investigate further how this mass repartitioning allows the simulation time step to be increased in a stable fashion without significantly increasing discretization error. To this end, we ran a set of simulations with different time steps and mass distributions on a three-residue peptide to get a comprehensive view of the effect of mass repartitioning and time step increase on a system whose accessible phase space is fully explored in a relatively short amt. of time. We next studied a 129-residue protein, hen egg white lysozyme (HEWL), to verify that the obsd. behavior extends to a larger, more-realistic, system. Results for the protein include structural comparisons from MD trajectories, as well as comparisons of pKa calcns. via const.-pH MD. We also calcd. a potential of mean force (PMF) of a dihedral rotation for the MTS [(1-oxyl-2,2,5,5-tetramethyl-pyrroline-3-methyl)methanethiosulfonate] spin label via umbrella sampling with a set of regular MD trajectories, as well as a set of mass-repartitioned trajectories with a time step of 4 fs. Since no significant difference in kinetics or thermodn. is obsd. by the use of fast HMR trajectories, further evidence is provided that long-time-step HMR MD simulations are a viable tool for accelerating MD simulations for mols. of biochem. interest.
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      Using collective variables to drive molecular dynamics simulations
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      A software framework is introduced that facilitates the application of biasing algorithms to collective variables of the type commonly employed to drive massively parallel mol. dynamics (MD) simulations. The modular framework that is presented enables one to combine existing collective variables into new ones, and combine any chosen collective variable with available biasing methods. The latter include the classic time-dependent biases referred to as steered MD and targeted MD, the temp.-accelerated MD algorithm, as well as the adaptive free-energy biases called metadynamics and adaptive biasing force. The present modular software is extensible, and portable between commonly used MD simulation engines.
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      Comer, J.; Gumbart, J. C.; Hénin, J.; Lelièvre, T.; Pohorille, A.; Chipot, C. The Adaptive Biasing Force Method: Everything You Always Wanted To Know but Were Afraid To Ask J. Phys. Chem. B 2015, 119, 1129– 1151 DOI: 10.1021/jp506633n
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      The Adaptive Biasing Force Method: Everything You Always Wanted To Know but Were Afraid To Ask
      Comer, Jeffrey; Gumbart, James C.; Henin, Jerome; Lelievre, Tony; Pohorille, Andrew; Chipot, Christophe
      Journal of Physical Chemistry B (2015), 119 (3), 1129-1151CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
      In the host of numerical schemes devised to calc. free energy differences by way of geometric transformations, the adaptive biasing force algorithm has emerged as a promising route to map complex free-energy landscapes. It relies upon the simple concept that as a simulation progresses, a continuously updated biasing force is added to the equations of motion, such that in the long-time limit it yields a Hamiltonian devoid of an av. force acting along the transition coordinate of interest. This means that sampling proceeds uniformly on a flat free-energy surface, thus providing reliable free-energy ests. Much of the appeal of the algorithm to the practitioner is in its phys. intuitive underlying ideas and the absence of any requirements for prior knowledge about free-energy landscapes. Since its inception in 2001, the adaptive biasing force scheme has been the subject of considerable attention, from in-depth math. anal. of convergence properties to novel developments and extensions. The method has also been successfully applied to many challenging problems in chem. and biol. In this contribution, the method is presented in a comprehensive, self-contained fashion, discussing with a crit. eye its properties, applicability, and inherent limitations, as well as introducing novel extensions. Through free-energy calcns. of prototypical mol. systems, many methodol. aspects are examd., from stratification strategies to overcoming the so-called hidden barriers in orthogonal space, relevant not only to the adaptive biasing force algorithm but also to other importance-sampling schemes. On the basis of the discussions in this paper, a no. of good practices for improving the efficiency and reliability of the computed free-energy differences are proposed.
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      Darve, E.; Rodriguez-Gomez, D.; Pohorille, A. Adaptive biasing force method for scalar and vector free energy calculations J. Chem. Phys. 2008, 128144120 DOI: 10.1063/1.2829861
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      Adaptive biasing force method for scalar and vector free energy calculations
      Darve, Eric; Rodriguez-Gomez, David; Pohorille, Andrew
      Journal of Chemical Physics (2008), 128 (14), 144120/1-144120/13CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)
      In free energy calcns. based on thermodn. integration, it is necessary to compute the derivs. of the free energy as a function of one (scalar case) or several (vector case) order parameters. We derive in a compact way a general formulation for evaluating these derivs. as the av. of a mean force acting on the order parameters, which involves first derivs. with respect to both Cartesian coordinates and time. This is in contrast with the previously derived formulas, which require first and second derivs. of the order parameter with respect to Cartesian coordinates. As illustrated in a concrete example, the main advantage of this new formulation is the simplicity of its use, esp. for complicated order parameters. It is also straightforward to implement in a mol. dynamics code, as can be seen from the pseudo-code given at the end. We further discuss how the approach based on time derivs. can be combined with the adaptive biasing force method, an enhanced sampling technique that rapidly yields uniform sampling of the order parameters, and by doing so greatly improves the efficiency of free energy calcns. Using the backbone dihedral angles Φ and Ψ in N-acetylalanyl-N'-methylamide as a numerical example, we present a technique to reconstruct the free energy from its derivs., a calcn. that presents some difficulties in the vector case because of the statistical errors affecting the derivs. (c) 2008 American Institute of Physics.
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      Hénin, J.; Chipot, C. Overcoming free energy barriers using unconstrained molecular dynamics simulations J. Chem. Phys. 2004, 121, 2904– 2914 DOI: 10.1063/1.1773132
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      Overcoming free energy barriers using unconstrained molecular dynamics simulations
      Henin, Jerome; Chipot, Christophe
      Journal of Chemical Physics (2004), 121 (7), 2904-2914CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)
      Assocn. of unconstrained mol. dynamics (MD) and the formalisms of thermodn. integration and av. force [Darve and Pohorille, J. Chem. Phys. 115, 9169 (2001)] have been employed to det. potentials of mean force. When implemented in a general MD code, the addnl. computational effort, compared to other std., unconstrained simulations, is marginal. The force acting along a chosen reaction coordinate ξ is estd. from the individual forces exerted on the chem. system and accumulated as the simulation progresses. The estd. free energy deriv. computed for small intervals of ξ is canceled by an adaptive bias to overcome the barriers of the free energy landscape. Evolution of the system along the reaction coordinate is, thus, limited by its sole self-diffusion properties. The illustrative examples of the reversible unfolding of deca-L-alanine, the assocn. of acetate and guanidinium ions in water, the dimerization of methane in water, and its transfer across the water liq.-vapor interface are examd. to probe the efficiency of the method.
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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.7b00675.

    • Effect of type I porcine collagen, up to 2.5 μM, on the absorption spectra of 10 μM RB; representative circular dichroism spectra for a 1.25 μM rose Bengal solution with or without 5.0 μM type I collagen; isothermal titration calorimetry measurements for binding of rose Bengal to a collagen-like peptide (CLP); ζ potential measurements for 2.5 μM type I collagen in 10 mM pH 5.0 MES buffer in the presence of different rose Bengal concentrations; schematic representation for the preparation of RB containing collagen hydrogels; photodecomposition of rose Bengal (125 μM) under oxygen, air, and nitrogen saturated solutions; photodecomposition of RB (125 μM) in the presence of 1.25 mM sodium ascorbate in oxygen, air, and nitrogen saturated solutions; triplet transient lifetime and quenching of RB excited state in the presence of different quenchers; tryptophan degradation mediated by green light exposure in the RB containing collagen matrix (PDF)


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