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

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 almost perfectly cancel out in the solvation free energies and because of that the solvation free energies of polar side chains remain largely unaffected by the peptide backbone. Aqueous ionic solutions have vast applications from protein folding to colloidal stability, water surface tension, osmotic property. Ion specificity in protein precipitation and ion specific propensity toward air-water and hydrophobic interfaces are well known. Most of the studies focus on the single ion behavior. The nature of ion-ion interaction near those mentioned water interfaces has not been well investigated. In chapter 5, ion pairing of halide anions with K+ , Na+ and Cs+ is studied in bulk water and near to a model hydrophobic surface (graphite) to shed some more knowledge on ion specific phenomena. Small sized cations tend to pair strongly with small sized anions near hydrophobic interfaces compared with that in bulk water, whereas ion-pairing for salts with small(cation)-large(anion) combinations and large-large ion combinations is affected in a lesser extend. The solvent shared ion pair state is the ion-pairing mode that becomes more favorable owing to the higher ion-ion association near hydrophobic interfaces. Ion- ion association free energy profile is further decomposed into entropic and enthalpic components for better molecular level understanding. A positive entropic component in the free energy of the solvent shared and contact ion pair states near graphite surface is found alike in bulk solution. Hydrophobic association near graphite interface is also analyzed. The contact pair state becomes more favorable because of that the overall association is more feasible near hydrophobic interfaces. The electrostatic interaction between the surface charge from protein and the ion from ionic solution is another important aspect that also contributes significantly in peptide or protein stability. Negatively charged acetate group from glutamate and aspartate side-chains can bind specifically with different cations that contributes to ion specific protein-cation interaction. In chapter 6, the structural details and the free-energy, entropy and enthalpy of ion-pairing between acetate ion, a model charge group present in protein or peptide and cations, K+ , Na+ , Li+ are discussed. The different affinities of Na+ and K+ toward acetate anion is explained using an enthalpy-entropy reinforcement mechanism at solvent shared ion-pair (SIP) state which involves a water-mediated hydrogen bonding interaction between the oppositely charged ions. Finally in chapter 7, we conclude the thesis and provide some future outlook