Atomically detailed simulations of concentrated protein solutions: the effects of salt, pH, point mutations, and protein concentration in simulations of 1000-molecule systems.

An ability to accurately simulate the dynamic behavior of concentrated macromolecular solutions would be of considerable utility in studies of a wide range of biological systems. With this goal in mind, a Brownian dynamics (BD) simulation method is reported here that allows systems to be modeled that comprise in excess of 1000 protein molecules, all of which are treated in atomic detail. Intermolecular forces are described in the method using an energy function that incorporates electrostatic and hydrophobic interactions and that is calibrated to reproduce experimental thermodynamic information with a single adjustable parameter. Using the method, BD simulations have been performed over a wide range of pH and ionic strengths for three proteins: hen egg white lysozyme (HEWL), chymotrypsinogen, and T4 lysozyme. The simulations reproduce experimental trends in second virial coefficients (B(22)) and translational diffusion coefficients, correctly capture changes in B(22) values due to single amino acid substitutions, and reveal a new explanation for the difficulties reported previously in the literature in reproducing B(22) values for protein solutions of very low ionic strength. In addition, a strong correlation is found between a residue's probability of being involved in a protein-protein contact in the simulations and its probability of being involved in an experimental crystal contact. Finally, exploratory simulations of HEWL indicate that the simulation model also gives a promising description of behavior at very high protein concentrations (approximately 250 g/L), suggesting that it may provide a suitable computational framework for modeling the complex behavior exhibited by macromolecules in cellular conditions.