Understanding structural features of biomolecular interactions : from classical simulations to ab initio calculations

Sammanfattning: The structures of biomolecules and their interactions dictate their functions. In this thesis, five papers are presented to illustrate how the dynamics of biomolecules can be investigated and derivation of desired thermodynamic quantities obtained by utilising a diverse range of computational techniques, from simulations utilising classical mechanical descriptions to calculations employing quantum mechanical descriptions. Classical simulation, referring to molecular dynamics simulation with atomistic force fields, has been used in every paper in this thesis. In Paper I, classical simulation and homology modelling are used to investigate the dynamics of a protein as well as that of its homologues, which have a missing region. Protein purification and production of these homologues was also attempted. When state transitions like protonation and tautomerisation equilibria are central to the query, we employed lambda-dynamics, an extension to conventional simulation that can describe transitions between states by including coupling parameter lambda in the dynamics. In Papers II and III, protonation and tautomerisation equilibria respectively are central to the query. In Paper II, lambda-dynamics and multiple pH regime are both used to calculate the pK shifts of cytidine in triplex nucleic acid environments. In some of the triplex nucleic acid systems, sugar modification LNA is present. The force field parameters of LNA have been updated to provider better descriptions for pK calculations. In Paper III, lambda-dynamics is used to describe tautomerisation equilibrium between two tautomers of pseudoisocytidine in singlestranded and triple-stranded nucleic acids in order to observe how the equilibrium shifts in different environments. In vitro binding assay is used to corroborate the computational results. When greater accuracy for certain properties like electrostatics or energetics is required, we employed quantum mechanical calculations as well as hybrid methods which combine classical and quantum mechanical descriptions. In Paper IV, QM and QM/MM calculations were performed to calculate the energetic difference between two tautomers in the ribosome. In Paper V, protein-specific polarised charge, a charge update scheme that updates the atomic charges with QM and Poisson-Boltzmann calculations during classical simulation, is used for better electrostatics description of a peptide.