Measurement and molecular modeling of protein-protein interactions in aqueous solutions

In this thesis, we examine the role of hydration in mediating protein-protein interactions and protein stability through experimental measurements complemented by molecular modeling and simulation. Our goal is to develop a robust model for protein-protein interactions that is faithful to the molecular details of protein structure, including hydration.; To this end, we adopt a quasi-chemical (QC) view of hydration in which solvent water molecules that strongly associate with the protein are treated explicitly, whereas a continuum description suffices for the remaining water. We successfully apply this QC description to the simplest case of predicting the hydration free energy of a water molecule. This application leads to insights into the subtle balance between strong "chemical-like" interactions between water molecules and packing effects due to the hydration structure around the solute. We extend this QC description to the study of conformational equilibria of alanine dipeptide (AD) in water. Our results show that the effect of hydration on the conformational preference of AD can be described by focusing on just four water molecules strongly associated with its polar groups.; For protein-protein interactions in aqueous solution, we extend an earlier model of Neal et al. [1], which captures the essential features of protein surface complementarity, but does not include a molecular description of hydration. In the context of our QC description of hydration, it is natural to treat strongly associated water molecules as a part of protein itself. Therefore, protein-protein interactions in the new model are described in terms of quasi-components comprised of the protein and bound water molecules immersed in a continuum solvent.; We test this new model by predicting osmotic second virial coefficient obtained by static light scattering (SLS) for lysozyme, staphylococcal nuclease and chymotrypsinogen solutions across a range of pH from 5.0 to 9.0 and ionic strengths up to 0.1M NaCl. Excellent agreement is obtained between predicted and measured second virial coefficients at all solution conditions, but only when strongly bound waters are included in the model. (Abstract shortened by UMI.)...