Experimental Benchmarks for Protein/Water Force Fields

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DESCRIPTION (provided by applicant): We seek support for a combined theoretical and experimental program that will advance our solution scattering experiments, molecular dynamics simulations, and theoretical analysis expertise, further into the area of pure water and aqueous hydration for both model protein systems and for molten globule proteins. We propose to conduct high quality scattering experiments and appropriate theoretical analysis on pure water away from ambient conditions, and to study aqueous amino acid monomer solutions using simulations and scattering experiments to determine the free energy of association of a variety of monomeric and some trimeric amino acids in water. The experimentally determined solvation of amino acid monomers will be extended to real protein chains by considering the role of hydration in stabilizing molten globule intermediates of various lysozymes and a-lactalbumin. We propose to simulate and perform neutron solution scattering experiments on labeled forms of both the native and molten globule forms of the lysozyme fold class to experimentally determine differences in intensity that arise from different structural organization of the hydrophobic core under native and molten globule conditions. The benchinarking of protein simulations as to the quality of the underlying empirical force fields is naturally addressed in the simulation and experimental research proposed here.