Introducing Molecular Flexibility in Efficient Simulations of Many-Protein Systems

A novel multiple conformations Monte Carlo (mcMC) computational method is presented that allows the modeling of protein-protein interaction and aggregation. Such processes are relevant in realistic biological environments, such as the cytoplasm and the extracellular matrix, which are characterized by high concentrations of biomolecular solutes, e.g. of 300-400 mg/mL for proteins and RNA in the cytoplasm of E. coli. Simulation of such environments necessitates the inclusion of a large number of protein molecules and therefore computationally inexpensive methods, such as rigid-body Brownian dynamics (BD) and Monte Carlo (MC) methods, must be used. However, the rigid-body representation typically employed in simulations of many-protein systems give rise to certain artifacts in protein-protein interactions. We present a methodology that allows us to incorporate molecular flexibility in MC simulations at low computational cost, and thereby eliminate ambiguities based on the structure selection in rigid molecule simulations. We benchmark and validate the methodology on solutions of hen egg white lysozyme (HEWL), an extraordinarily well-studied system for which extensive experimental data, including osmotic virial coefficients, solution structure factors, and multiple structures determined by x-ray and neutron crystallography and solution NMR, as well as previous BD simulation results, are available