| Autor: |
Prytkova V; 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., Heyden M; 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., Khago D; 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., Freites JA; 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., Butts CT; 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., Martin RW; 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., Tobias DJ; 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. |
| Abstrakt: |
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. |
