Development of CHARMM Additive Potential Energy Parameters for α-Methyl Amino Acids
- Anthony J. PaneAnthony J. PaneLaboratory of Computational Biology, National Heart, Lung, and Blood Institute, National Institutes of Health, Rockville, Maryland 20892, United StatesMore by Anthony J. Pane
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- Wenbo YuWenbo YuDepartment of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, 20 Penn Street, Baltimore, Maryland 21201, United StatesMore by Wenbo Yu
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- Asaminew AytenfisuAsaminew AytenfisuDepartment of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, 20 Penn Street, Baltimore, Maryland 21201, United StatesMore by Asaminew Aytenfisu
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- Jude TunyiJude TunyiLaboratory of Computational Biology, National Heart, Lung, and Blood Institute, National Institutes of Health, Rockville, Maryland 20892, United StatesMore by Jude Tunyi
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- Richard M. VenableRichard M. VenableLaboratory of Computational Biology, National Heart, Lung, and Blood Institute, National Institutes of Health, Rockville, Maryland 20892, United StatesMore by Richard M. Venable
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- Alexander D. MacKerell Jr.Alexander D. MacKerell, Jr.Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, 20 Penn Street, Baltimore, Maryland 21201, United StatesMore by Alexander D. MacKerell, Jr.
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- Richard W. Pastor*Richard W. Pastor*Email: [email protected]. Phone: 301-435-2035.Laboratory of Computational Biology, National Heart, Lung, and Blood Institute, National Institutes of Health, Rockville, Maryland 20892, United StatesMore by Richard W. Pastor
Abstract
Potential energy parameters for α-methyl amino acids were generated with ab initio calculations on α-methyl-N-acetylalanyl-N′-methylamide (the α-methyl “alanine dipeptide”) which served as an input to a grid-based correction to the backbone torsional potential (known as CMAP) consistent with the CHARMM36m additive protein force field. The new parameters were validated by comparison with experimentally determined helicities of the 22 residue C-terminal peptide (H10) from apolipoprotein A1 and five α-methylated variants in water and 0.3:0.7 trifluoroethanol (TFE)/water. Conventional molecular dynamics simulation totaling 30 μs for each peptide is in overall good agreement with the experiment, including the increased helicity in 30% TFE. An additional 500 ns of simulation using two-dimensional dihedral biasing (bpCMAP) replica exchange reduced left-handed conformations, increased right-handed helices, and thereby mostly decreased agreement with the experiment. Analysis of side chain–side chain salt bridges suggests that the overestimation of the helical content may be, in part, due to such interactions. The increased helicity of the peptides in 30% TFE arises from decreased hydrogen bonding of the backbone atoms to water and a concomitant increase in intramolecular backbone hydrogen bonds.
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