Computational investigations of biomolecular conformational transitions: Ligand binding, transition pathways and key residues

Conformational transitions (i.e. structural changes) are an integral part of the functional cycle of many biomolecules and act as an important regulatory mechanism to keep cells functioning normally. There are a few interesting mechanistic questions for conformational transitions in general including the molecular mechanism of ligand binding, the dominant transition pathways and associated energetics and kinetics, and the key residues important for conformational transitions.;This dissertation aims to address these mechanistic questions with representative systems and problems using computational and simulation approaches. Specifically, in the aspect of ligand binding, the mechanism of non-covalent binding of salt ions and small solutes to peptides is investigated at the molecular level. Furthermore, the coupling behavior between DNA binding and disruption and formation of salt bridges in integration host factor (IHF) is also studied. As for dominant transition pathways, the activation mechanism (pathways) of a signaling protein CheY is explored at the atomic resolution with a synergistic combination of transition path sampling and free energy simulations. With the long-term goal of studying transition pathways for mechano-biological conformational transitions in general, a coarse grained computational framework combining continuum mechanics and continuum electrostatics is also developed. Moreover, to facilitate comparisons with experiments, the theoretical procedures for kinetic calculations of conformational transitions (the ion/solute conduction in particular) are also derived. Finally, the exploration of key residues for conformational transitions is discussed with the myosin motor domain as the model system.