Computational study of water and ion distributions around biomolecules
Creators: name: Nguyen, Hung Tien
Publisher: name: No Publisher Supplied
Year: 2016

description: Water and ions play a crucially important role in governing biomolecule structure, stability and function. Knowledge of how water molecules and ions distribute around proteins and nucleic acids at the molecular level has long been sought. Due to their highly mobile nature, the hydration water and ion cloud are very hard to probe with traditional experiment techniques such as X-ray crystallography, NMR or microscopy. Here we use a combination of computational approaches and X-ray scattering experiment to investigate the water and ion distribution around biomolecules.    In the first part, we describe a protocol to calculate X-ray scattering profiles from atomic models of macromolecules. We show that the quality of the Reference Interaction Site Model (RISM) hydration closely approaches those from explicit molecular dynamics simulation in terms of reproducing X-ray intensity signals. The intensity profiles (which involve no adjustable parameters) match experiment and molecular dynamics simulation up to wide angle for relatively rigid biomolecules. For nucleic acid structures, we demonstrate that an improvement in the intensity calculations could be made by using the conformational ensemble obtained from MD simulation rather than using a single diffraction structure.    In the second part, we extend the X-ray scattering theory and describe a novel analysis method to extract water and ion distribution from X-ray scattering experiment. The analysis complements recent experimental techniques, showing both numbers of excess solvent (water, ions) and aspects of their distributions around macromolecules. Comparisons between experimental and theoretically predicted distributions are made for molecular dynamics and RISM theory, showing that although the total X-ray patterns are very similar, the distributions from MD simulations are generally better than those from RISM. This illustrate the potential power of this analysis to guide the development of computational models of solvation.    Finally, we investigate a possible use of partial molar volume and number of excess solvent (extracted from X-ray experiment and from other direct measurements) as a guide to recalibrate force fields. The partial molar volume (and the number of excess solvent) can be conceptually divided into contributions of the solute excluded volume and hydration shell. While the former depends only on the solute topology and can be computed once the solute structure is known, the latter is more “interesting” and contains valuable information about solute-solvent interaction. We show that current protein force fields reproduce reasonably the hydration shell term although more works are needed to achieve better solute-solvent interaction balance. For nucleic acids, the solute-solvent interaction is strongly overestimated and a recalibration is needed. As a proof of concept, we reoptimize the non-bonded parameters for the phosphate groups in a DNA duplex and show that the predicted partial molar volume and the number of excess hydration water around the DNA approach the experimental value. Our parameters, however, currently cannot be used for dynamics study unless a complete refit of bonded parameters is carried out. Since the nucleic acid structure depends tightly on the solute-solvent interaction, we believe that such a misbalance should be corrected in the near future.