We develop a multiscale coarse-grain model of the NIST Monoclonal Antibody Reference Material 8671 (NISTmAb) to enable systematic computational investigations of high-concentration physical instabilities such as phase separation, clustering, and aggregation. Our multiscale coarse-graining strategy captures atomic-resolution interactions with a computational approach that is orders of magnitude more efficient than atomistic models, assuming the biomolecule can be decomposed into one or more rigid bodies with known, fixed structures. This method reduces interactions between tens of thousands of atoms to a single anisotropic interaction site. The anisotropic interaction between unique pairs of rigid bodies is precomputed over a discrete set of relative orientations and stored, allowing interactions between arbitrarily oriented rigid bodies to be interpolated from the precomputed table during coarse-grained Monte Carlo simulations. We present this approach for lysozyme and lactoferrin as a single rigid body and for the NISTmAb as three rigid bodies bound by a flexible hinge with an implicit solvent model. This coarse-graining strategy predicts experimentally measured radius of gyration and second osmotic virial coefficient data, enabling routine Monte Carlo simulation of medically relevant concentrations of interacting proteins while retaining atomistic detail. All methodologies used in this work are available in the open-source software Free Energy and Advanced Sampling Simulation Toolkit.
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7 September 2024
Research Article|
September 05 2024
Anisotropic coarse-grain Monte Carlo simulations of lysozyme, lactoferrin, and NISTmAb by precomputing atomistic models
Special Collection:
Monte Carlo methods, 70 years after Metropolis et al. (1953)
Harold W. Hatch
;
Harold W. Hatch
a)
(Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Validation, Visualization, Writing – original draft, Writing – review & editing)
1
Chemical Informatics Research Group, Chemical Sciences Division, National Institute of Standards and Technology
, Gaithersburg, Maryland 20899-8380, USA
a)Author to whom correspondence should be addressed: [email protected]
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Christina Bergonzo
;
Christina Bergonzo
(Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Validation, Visualization, Writing – original draft, Writing – review & editing)
2
Institute for Bioscience and Biotechnology Research
, Rockville, Maryland 20850, USA
3
Biomolecular Structure and Function Group, Biomolecular Measurement Division, National Institute of Standards and Technology
, Gaithersburg, Maryland 20899-8380, USA
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Marco A. Blanco
;
Marco A. Blanco
(Conceptualization, Funding acquisition, Methodology, Writing – review & editing)
4
Discovery Pharmaceutical Sciences, Merck Research Laboratories, Merck & Co., Inc.
, West Point, Pennsylvania 19486, USA
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Guangcui Yuan;
Guangcui Yuan
(Validation, Writing – review & editing)
5
Center for Neutron Research, National Institute of Standards and Technology
, Gaithersburg, Maryland 20899, USA
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Sergei Grudinin
;
Sergei Grudinin
(Methodology, Writing – review & editing)
6
CNRS, Grenoble INP, LJK, Université Grenoble Alpes
, 38000 Grenoble, France
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Mikael Lund
;
Mikael Lund
(Methodology, Writing – review & editing)
7
Division of Computational Chemistry, Lund University
, Lund, Sweden
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Joseph E. Curtis
;
Joseph E. Curtis
(Conceptualization, Methodology, Writing – review & editing)
8
NIST Center for Neutron Research, National Institute of Standards and Technology
, Gaithersburg, Maryland 20899, USA
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Alexander V. Grishaev
;
Alexander V. Grishaev
(Funding acquisition, Methodology, Project administration, Writing – review & editing)
2
Institute for Bioscience and Biotechnology Research
, Rockville, Maryland 20850, USA
3
Biomolecular Structure and Function Group, Biomolecular Measurement Division, National Institute of Standards and Technology
, Gaithersburg, Maryland 20899-8380, USA
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Yun Liu
;
Yun Liu
(Conceptualization, Funding acquisition, Project administration, Supervision, Writing – review & editing)
5
Center for Neutron Research, National Institute of Standards and Technology
, Gaithersburg, Maryland 20899, USA
9
Center for Neutron Science, Department of Chemical and Biomolecular Engineering, College of Engineering, University of Delaware
, Newark, Delaware 19711, USA
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Vincent K. Shen
Vincent K. Shen
(Conceptualization, Funding acquisition, Methodology, Project administration, Resources, Supervision, Writing – review & editing)
1
Chemical Informatics Research Group, Chemical Sciences Division, National Institute of Standards and Technology
, Gaithersburg, Maryland 20899-8380, USA
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a)Author to whom correspondence should be addressed: [email protected]
J. Chem. Phys. 161, 094113 (2024)
Article history
Received:
June 21 2024
Accepted:
August 16 2024
Citation
Harold W. Hatch, Christina Bergonzo, Marco A. Blanco, Guangcui Yuan, Sergei Grudinin, Mikael Lund, Joseph E. Curtis, Alexander V. Grishaev, Yun Liu, Vincent K. Shen; Anisotropic coarse-grain Monte Carlo simulations of lysozyme, lactoferrin, and NISTmAb by precomputing atomistic models. J. Chem. Phys. 7 September 2024; 161 (9): 094113. https://doi.org/10.1063/5.0224809
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