Advanced path sampling of the kinetic network of small proteins

This thesis is focused on developing advanced path sampling simulation methods to study protein folding and unfolding, and to build kinetic equilibrium networks describing these processes. In Chapter 1 the basic knowledge of protein structure and folding theories were introduced and a brief overview of molecular simulation on protein folding was given. Descriptions of molecular dynamics (MD) simulation techniques, Monte Carlo (MC) method and relevant analysis methods can be found in Chapter 2. An introduction to basic transition path sampling (TPS), transition interface sampling (TIS) and multiple state TPS/TIS can be found in Chapter 3. In Chapter 4, we applied the multiple state TPS/TIS to an alanine-dipeptide system. In Chapter 5, we optimize the path sampling strategy by allowing the exchange of interfaces and states. This advanced method, known as the single replica MSTIS method, allows us to build a converged transition network efficiently. In Chapter 6, we applied single replica MSTIS to a more complex Trpcage system in explicit solvent, where more than 10 states were identified and state-interfaces overlap problems had to be addressed. In Chapter 7, we applied this sophisticated method to another complex system, i.e. the 35-residue fragment villin headpiece (HP-35) in implicit solvent, where we managed to overcome huge unfolding barriers (on the sub-millisecond time scale) of the system. Those applications demonstrated that the advanced TPS methods are powerful tools for studying protein folding both efficiently and accurately.