Abstracts Biological Sciences

Molecular simulations of Hofmeister ion pairing and solvation of protein building blocks in aqueous interfacial environments

by Timir Hajari

In current days, computer simulation is a scientific tool to study material properties. Using computer simulation, equilibrium and nonequilibrium properties of materials can be estimated with a detailed atomistic picture which is not easily accessible with exper- imental techniques. It is widely used to get the atomistic resolution of various chemical and biophysical processes for better understanding of these processes. Molecular level understanding of stability, conformational changes and solvation properties of proteins or peptides in water or in ionic solution or in water-cosolvent (osmolytes) mixtures are research areas where lots of simulations and experimental works are ongoing. To understand these problems, we mainly focus in this thesis on two types of thermodynamic processes, solvation of different amino acid side-chains and ion pairing/ion-ion interaction in bulk water and near hydrophobic surfaces using molecular dynamics simulations. A detailed understanding of aqueous solvation of protein building blocks, namely amino acids, is very useful to understand the structural stability of proteins or peptides. The free energy estimation using molecular simulations is a useful tool to rationalize protein thermodynamics. In chapter 2, a short description of different methods to estimate free energies is presented. Most of the studies to understand thermodynamics of protein have used solvation data of small molecules or analogs as a representative of amino acid side-chains in protein or peptide. In reality, these side-chains are not free but rather attached to a peptide backbone. In chapter 3, we estimate the solvation free energy of different polar and nonpolar amino acid side-chains when they are attached to a peptide backbone to assess the reliability of such small molecules solvation data in explaining phenomena like protein folding and protein-protein association. We find all the nonpolar side-chains become remarkable less hydrophobic than what is expected from the solvation free energy data of the side-chain analogs. This finding challenges many hydrophobicity scales based on the solvation free energy data of small molecules. To analyze the origin of such reductions in hydrophobicity, solvation entropies and enthalpies of nonpolar and polar side chains in peptide backbone are also estimated in chapter 4. Solvation entropies of nonpolar side-chains in peptide backbone are found to be less unfavorable than solvation entropies of free side-chains which causes an overall hydrophobicity reduction. Cavity and dispersion contributions in the solvation free energies of nonpolar side-chains are also estimated. We find that a nonpolar side-chain sized cavity formation next to a tripeptide backbone is entropically favored over formation of similar sized cavities in bulk water, which effectively makes nonpolar side-chains less hydrophobic. The solvation enthalpies and entropies of the polar side chains are negative, but in absolute magnitude smaller compared with the corresponding analogue data. These effects… Advisors/Committee Members: van der Vegt, Nico (advisor), Böhm, Michael C. (advisor), Biesalski, Markus (advisor), Plenio, Herbert (advisor).