Investigations Of Solvent Effect On Enthalpic Pairwise Interactions Of Small Chiral Molecules And Interactions Of Two Drugs With Human Serum Albumin

As the molecular essentials for the biological regulation of organism, the interactions between small molecules and biomacromolecules are of great importance to understand the mechanism of bioregulation. Amino acids, small peptides and their derivatives etc., which are considered to be a variety of biological model compounds, have been drawing growing interests among biophysical chemists due to their value in supplying information on solute-solute, solvent-solute interactions and long-range intramolecular interactions as well as their role in revealing the essential of noncovalent interactions which are necessary to illuminate protein folding. This dissertation consists of the following four parts.In the first part, two representative amino acids (L-alanine and L-serine) which bear typical hydrophobic and hydrophilic side-chains respectively were chosen as research objects. By using isothermal titration microcalorimetry (ITC), dilution enthalpies of the two amino acids in pure water and in organic solvent-water mixtures (DMSO-H₂O and DMF-H₂O) of various mass fractions have been determined. The results have been analyzed by the excess thermodynamic function concept. Homogenous enthalpic interaction coefficients have been calculated according to the McMillan-Mayer's statistical thermodynamics approach. The relationship between the composition of mixed solvents and the enthalpic pairwise interaction coefficient were examined thoroughly to explore the possible fashion of solute-solute interactions or solvent-solvent interactions in these systems.In the second part, two types of chiral aliphatic alcohols (momohydric and dihydric alcohols) which contains mono-chiral center and di-chiral centers respectively in their molecular skelecton, namely R-2-butanol, S-2-butanol, (2R,4R)-(?)-2,4-dihydric pentanol, (2S,4S)-(+)-2,4-dihydric pentanol, were chosen as research objects. The enthalpies of dilution of these chiral alcohols in pure water, in pure organic solvents such as methanol and ethanol, as well as in aqueous urea solutions of different concentrations have been determined respectively by ITC.In the third part, typical biomacromolecule human serum albumin (HSA) and drug molecule propranolol were chosen as research objects. The interaction thermodynamic properties such as association positions, interaction types, association equilibrium constant, enthalpy and entropy between HSA and propranolol have been investigated by ITC.In the fourth part, the interaction of HSA with a dye molecule alizarin HSA been studied by fluorescence spectroscopy assisted with molecule docking technology based on B3LYP/6-31G*. The apparent binding constants Kq and thermodynamic parameters at 298 K and 302 K were calculated respectively. In addition, the study of computational modeling indicated that alizarin can bind to the siteâ… B of HSA and hydrophobic interaction is the major force in the binding site. The potential energy of interaction is -23.557 kJ/mol. The aromatic amino acids of the protein including Tyr161, Phe157, Phe149 and His146 all lie in the hydrophobic interaction cavity. This is in good agreement with the result of the fluorescence experiments.