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43463-AC4
Coarse-Grained Molecular Models of Mixed-Aqueous Solvents

Christopher J. Roberts, University of Delaware

This project sought to develop a coarse-grained model of mixed-aqueous solvents for use by those interested in using molecular simulation methods to study supermolecular self-assembly of macromolecules such as proteins, polypeptides, and polymers in aqueous solution under conditions where implicit solvent models are inadequate either due to a lack of structural detail, or because they are limited to primarily (pure) water as the solvent. The need to be able to simultaneously treat the solvent and multiple (~10-100) conformationally flexible macromolecules poses a major challenge for conventional “all-atom” methods, as well as for standard coarse-grained, rigid-body approaches such as Brownian dynamics. The focus of this project was on coarse-grained solvent models that are amenable to rapid macromolecular simulation techniques such as discontinuous molecular dynamics and (pseudo-)rigid-body simulations of concentrated solutions of protein and polypeptide chains.

The major focus in the last year has been on optimization of intermolecular interaction parameters for the model(s) to provide good agreement with experimental data for phase behavior and hydrophobe solubility in pure water and binary water-polyol mixtures, and on adapting available simulation methods and free energy biasing approaches for more efficient thermophysical property calculations of multi-atom, hard-body systems with highly directional and strong short-ranged attractions such as hydrogen bonds. In the process of pursuing this we have identified a new, multi-scale molecular simulation method and have been developing this in parallel with a semi-analytical approach for the statistical thermodynamics and structure of complex molecular fluids and colloidal systems. We are currently in the process of validating the new method against canonical systems, and plan to publish those results as a general method for use in phase behavior calculations for large systems and systems with complex interaction potentials. The methods will also be used to more efficiently complete the refinement of interaction parameters of our water and water-cosolvent models that are the original focus of this project. The results of that work are planned for separate publication in the near future. The parallel work with development of a semi-analytical approach that was noted above was cofunded by PRF, and the first publication to result from that work (cited below) employed a simple lattice-fluid mimic of attractive colloids with isotropic or anisotropic potentials of mean force.

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