Analyzing and Enhancing Molecular Dynamics Through the Synergy of Physics and Artificial Intelligence

Abstract

Rapid advances in computational power have made all-atom molecular dynamics (MD) a powerful tool for studying systems in biophysics, chemical physics and beyond. By solving Newton's equations of motion in silico, MD simulations allow us to track the time evolution of complex molecular systems in an all-atom, femtosecond resolution, enabling the evaluation of both their thermodynamic and kinetic properties. Though MD simulations are powerful, their effectiveness is often hampered by the large amount of data they produce. For instance, a standard microsecond-long simulation of a protein can easily generate hundreds of gigabytes of data, which can be difficult to analyze. Moreover, the time required to conduct these simulations can be prohibitively long. Microsecond-long simulations often take weeks to complete, whereas the processes of interest may occur on the timescale of milliseconds or even hundreds of seconds. These factors collectively pose significant challenges in leveraging MD simulations for comprehensive analysis and exploration of chemical and biological systems. In this thesis, I address these challenges by leveraging physics-inspired insights to learn unique, useful, and also meaningful low-dimensional representations of complex molecular systems. These representations enable effective analysis and interpretation of the vast amount of data generated from experiments and simulations. These representations have proven to be valuable in providing mechanistic insights into some fundamental problems within theoretical chemistry and biophysics, such as understanding the interplay between long-range and short-range forces in ion pair dissociation and the transformation of proteins from unstable random coils to structured forms. Furthermore, these physics-informed representations play a crucial role in enhancing MD simulations. They facilitate the construction of simplified kinetic models, enabling the generation of dynamical trajectories spanning significantly longer time scales than those accessible by conventional MD simulations. Additionally, they can serve as blueprints to guide the sampling process in combination with existing enhanced sampling methods. Through this thesis, I showcase how the synergy between physics and AI can advance our understanding of molecular systems and facilitate more efficient and insightful analysis in the fields of computational chemistry and biophysics.