Development of Algorithms to Enhance Sampling of Free Energy Landscape Underlying Chemical and Biological Processes

• Main Author: Yeqing, Yu
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2021
• Subjects: Chemistry
• ISBN: 9798209876212

Conformational dynamics play an important role for biological macromolecules to perform their functions and underline numerous biochemical processes. With the rapid development of computational approaches, computer simulations such as molecular dynamics (MD) simulations provide an important auxiliary means for the experiment. However, it remains challenging for MD simulations to reach the experimentally relevant timescales and fully sample the free energy landscapes that govern the motions of biomolecules. Milestoning is a popular enhanced sampling algorithm that can bridge this timescale gap, and obtain thermodynamics and kinetics of long-timescale molecular processes from many short MD simulations. In Milestoning, the conformational space between the initial and final state are divided into cells, and short simulations are then initiated to sample transitions between adjacent cell boundaries or milestones. Therefore, the locations of milestones are key to achieve high computational efficiency in milestoning. However, existing studies mostly adopt a simple approach by equally placing milestones along one or two reaction coordinates connecting the initial and final state. In the first part of my thesis, we present three new schemes to optimize the locations of milestones and demonstrate that they can all greatly enhance the efficiency of milestoning. In the second part of the thesis, I presented a new free energy functional that couples with the solvation model via the Integral Equation Theory. Using YBG free energy functional, we can compute the solvation free energy of drug-like compounds in water and various organic solvents at a high accuracy. At the final part of my thesis, I describe a study to analyze the binding affinity of luminescent molecules by combining free energy calculation and experiment.