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Hybrid Kinetic Monte Carlo/Molecular Dynamics Simulations of Bond Scissions in Proteins

  • Benedikt Rennekamp
    Benedikt Rennekamp
    Heidelberg Institute for Theoretical Studies, Schloss-Wolfsbrunnenweg 35, 69118 Heidelberg, Germany
    Institute for Theoretical Physics, Heidelberg University, Philosophenweg 16, 69120 Heidelberg, Germany
  • Fabian Kutzki
    Fabian Kutzki
    Heidelberg Institute for Theoretical Studies, Schloss-Wolfsbrunnenweg 35, 69118 Heidelberg, Germany
    Institute of Physical Chemistry, Karlsruhe Institute of Technology, Fritz-Haber-Weg 2, 76131 Karlsruhe, Germany
  • Agnieszka Obarska-Kosinska
    Agnieszka Obarska-Kosinska
    Heidelberg Institute for Theoretical Studies, Schloss-Wolfsbrunnenweg 35, 69118 Heidelberg, Germany
    Hamburg Unit c/o DESY, European Molecular Biology Laboratory, Notkestrasse 85, 22607 Hamburg, Germany
  • Christopher Zapp
    Christopher Zapp
    Heidelberg Institute for Theoretical Studies, Schloss-Wolfsbrunnenweg 35, 69118 Heidelberg, Germany
    Institute for Theoretical Physics, Heidelberg University, Philosophenweg 16, 69120 Heidelberg, Germany
  • , and 
  • Frauke Gräter*
    Frauke Gräter
    Heidelberg Institute for Theoretical Studies, Schloss-Wolfsbrunnenweg 35, 69118 Heidelberg, Germany
    Interdisciplinary Center for Scientific Computing, Heidelberg University, INF 205, 69120 Heidelberg, Germany
    *E-mail: [email protected]; Phone: +49-6221-533267.
Cite this: J. Chem. Theory Comput. 2020, 16, 1, 553–563
Publication Date (Web):November 18, 2019
https://doi.org/10.1021/acs.jctc.9b00786
Copyright © 2019 American Chemical Society

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    Abstract

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    Proteins are exposed to various mechanical loads that can lead to covalent bond scissions even before macroscopic failure occurs. Knowledge of these molecular breakages is important to understand mechanical properties of the protein. In regular molecular dynamics (MD) simulations, covalent bonds are predefined, and reactions cannot occur. Furthermore, such events rarely take place on MD time scales. Existing approaches that tackle this limitation either rely on computationally expensive quantum calculations (e.g., QM/MM) or complex bond order formalisms in force fields (e.g., ReaxFF). To circumvent these limitations, we present a new reactive kinetic Monte Carlo/molecular dynamics (KIMMDY) scheme. Here, bond rupture rates are calculated based on the interatomic distances in the MD simulation and then serve as an input for a kinetic Monte Carlo step. This easily scalable hybrid approach drastically increases the accessible time scales. Using this new technique, we investigate bond ruptures in a multimillion atom system of tensed collagen, a structural protein found in skin, bones, and tendons. Our findings show a clear concentration of bond scissions near chemical cross-links in collagen. We also examine subsequent dynamic relaxation steps. Our method exhibits only a minor slowdown compared to classical MD and is straightforwardly applicable to other complex (bio)materials under load and related chemistries.

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jctc.9b00786.

    • Supplementary Figure 1: Estimation of changes in partial charges before and after bond rupture with Mulliken population analysis based on orbitals. Supplementary Figure 2: Estimating the impact of nonbonded interactions between the atoms formerly involved in a bond after the breakage (PDF)

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    Cited By

    This article is cited by 8 publications.

    1. Lara A. Patel, Phuong Chau, Serena Debesai, Leah Darwin, Chris Neale. Drug Discovery by Automated Adaptation of Chemical Structure and Identity. Journal of Chemical Theory and Computation 2022, 18 (8) , 5006-5024. https://doi.org/10.1021/acs.jctc.1c01271
    2. Ikuo Kurisaki, Shigenori Tanaka. Reaction Pathway Sampling and Free-Energy Analyses for Multimeric Protein Complex Disassembly by Employing Hybrid Configuration Bias Monte Carlo/Molecular Dynamics Simulation. ACS Omega 2021, 6 (7) , 4749-4758. https://doi.org/10.1021/acsomega.0c05579
    3. Kai Riedmiller, Patrick Reiser, Elizaveta Bobkova, Kiril Maltsev, Ganna Gryn'ova, Pascal Friederich, Frauke Gräter. Substituting density functional theory in reaction barrier calculations for hydrogen atom transfer in proteins. Chemical Science 2024, 15 (7) , 2518-2527. https://doi.org/10.1039/D3SC03922F
    4. Benedikt Rennekamp, Christoph Karfusehr, Markus Kurth, Aysecan Ünal, Debora Monego, Kai Riedmiller, Ganna Gryn’ova, David M. Hudson, Frauke Gräter. Collagen breaks at weak sacrificial bonds taming its mechanoradicals. Nature Communications 2023, 14 (1) https://doi.org/10.1038/s41467-023-37726-z
    5. Emanuel K. Peter, Dietmar J. Manstein, Joan-Emma Shea, Alexander Schug. CORE-MD II: A fast, adaptive, and accurate enhanced sampling method. The Journal of Chemical Physics 2021, 155 (10) https://doi.org/10.1063/5.0063664
    6. Agnieszka Obarska-Kosinska, Benedikt Rennekamp, Aysecan Ünal, Frauke Gräter. ColBuilder: A server to build collagen fibril models. Biophysical Journal 2021, 120 (17) , 3544-3549. https://doi.org/10.1016/j.bpj.2021.07.009
    7. Gary S. Kedziora, James Moller, Rajiv Berry, Dhriti Nepal. Ab initio molecular dynamics modeling of single polyethylene chains: Scission kinetics and influence of radical under mechanical strain. The Journal of Chemical Physics 2021, 155 (2) https://doi.org/10.1063/5.0047371
    8. Christopher Zapp, Agnieszka Obarska-Kosinska, Benedikt Rennekamp, Markus Kurth, David M. Hudson, Davide Mercadante, Uladzimir Barayeu, Tobias P. Dick, Vasyl Denysenkov, Thomas Prisner, Marina Bennati, Csaba Daday, Reinhard Kappl, Frauke Gräter. Mechanoradicals in tensed tendon collagen as a source of oxidative stress. Nature Communications 2020, 11 (1) https://doi.org/10.1038/s41467-020-15567-4

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