title: Multi-Conformation Monte Carlo: A Method for Introducing Flexibility in Efficient Simulations of Many-Protein Systems.
abstract: We present a novel multi-conformation Monte Carlo simulation method that enables the modeling of protein-protein interactions and aggregation in crowded protein solutions. This approach is relevant to a molecular-scale description of realistic biological environments, including the cytoplasm and the extracellular matrix, which are characterized by high concentrations of biomolecular solutes (e.g., 300-400 mg/mL for proteins and nucleic acids in the cytoplasm of Escherichia coli). Simulation of such environments necessitates the inclusion of a large number of protein molecules. Therefore, computationally inexpensive methods, such as rigid-body Brownian dynamics (BD) or Monte Carlo simulations, can be particularly useful. However, as we demonstrate herein, the rigid-body representation typically employed in simulations of many-protein systems gives rise to certain artifacts in protein-protein interactions. Our approach allows us to incorporate molecular flexibility in Monte Carlo simulations at low computational cost, thereby eliminating ambiguities arising from structure selection in rigid-body simulations. We benchmark and validate the methodology using simulations of hen egg white lysozyme in solution, a well-studied system for which extensive experimental data, including osmotic second virial coefficients, small-angle scattering structure factors, and multiple structures determined by X-ray and neutron crystallography and solution NMR, as well as rigid-body BD simulation results, are available for comparison.
authors.affiliation: Department of Chemistry, ‡Department of Sociology, §Department of Statistics, ∥Department of Electrical Engineering and Computer Science, and ⊥Department of Molecular Biology and Biochemistry, University of California, Irvine , Irvine, California 92697, United States.
authors.forename: Vera
authors.initials: V
authors.lastname: Prytkova
authors.affiliation: Department of Chemistry, ‡Department of Sociology, §Department of Statistics, ∥Department of Electrical Engineering and Computer Science, and ⊥Department of Molecular Biology and Biochemistry, University of California, Irvine , Irvine, California 92697, United States.
authors.forename: Matthias
authors.initials: M
authors.lastname: Heyden
authors.affiliation: Department of Chemistry, ‡Department of Sociology, §Department of Statistics, ∥Department of Electrical Engineering and Computer Science, and ⊥Department of Molecular Biology and Biochemistry, University of California, Irvine , Irvine, California 92697, United States.
authors.forename: Domarin
authors.initials: D
authors.lastname: Khago
authors.affiliation: Department of Chemistry, ‡Department of Sociology, §Department of Statistics, ∥Department of Electrical Engineering and Computer Science, and ⊥Department of Molecular Biology and Biochemistry, University of California, Irvine , Irvine, California 92697, United States.
authors.forename: J Alfredo
authors.initials: JA
authors.lastname: Freites
authors.affiliation: Department of Chemistry, ‡Department of Sociology, §Department of Statistics, ∥Department of Electrical Engineering and Computer Science, and ⊥Department of Molecular Biology and Biochemistry, University of California, Irvine , Irvine, California 92697, United States.
authors.forename: Carter T
authors.initials: CT
authors.lastname: Butts
authors.affiliation: Department of Chemistry, ‡Department of Sociology, §Department of Statistics, ∥Department of Electrical Engineering and Computer Science, and ⊥Department of Molecular Biology and Biochemistry, University of California, Irvine , Irvine, California 92697, United States.
authors.forename: Rachel W
authors.initials: RW
authors.lastname: Martin
authors.affiliation: Department of Chemistry, ‡Department of Sociology, §Department of Statistics, ∥Department of Electrical Engineering and Computer Science, and ⊥Department of Molecular Biology and Biochemistry, University of California, Irvine , Irvine, California 92697, United States.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Tobias
mesh_terms: D000818:Animals; D016477:Artifacts; D019985:Benchmarking; D002645:Chickens; D003461:Crystallography; D003593:Cytoplasm / Q000737:chemistry*; D004926:Escherichia coli / Q000737:chemistry; D029968:Escherichia coli Proteins / Q000737:chemistry*; D005109:Extracellular Matrix / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D009010:Monte Carlo Method; D009113:Muramidase / Q000737:chemistry*; D011487:Protein Conformation; D013816:Thermodynamics
chemical_list: D029968:Escherichia coli Proteins; C421864:hen egg lysozyme; D009113:Muramidase