Computational modeling and automation techniques to study biomolecular dynamics

Physically-principled computational modeling and automation techniques have emerged as potent methodologies in exploring biomolecular dynamics and generating experimentally-testable hypotheses. In this dissertation, we develop a set of simulation automation techniques and present results on case studies of biomolecular simulation. Nucleosomes form the fundamental building blocks of eukaryotic chromatin. We use multiscale modeling and discrete molecular dynamics simulations to investigate the dynamics of the Xenopus laevis nucleosome core particle, the fundamental unit of chromatin. Histone tails are flexible and are poorly resolved in X-ray crystal structures. We probe how molecular-level dynamics of the histone tails, core histones and associated DNA mediate chromatin stability at the scale of single-nucleosomes. Based on the positional fluctuations of core histone residues, we postulate cold sites, a set of core histone residues essential for stabilizing the Xenopus laevis nucleosome core particle. We explore changes in the biophysical stability of mono-nucleosomes by designing mutations in core histones and using Medusa, a high-throughput computational technique to explore changes in mononucleosomal stability resulting from point mutations. The presence of centromere-specific H3 variant histone (Cse4) in centromere-specific nucleosomes defines the kinetochore locus. However, structural details of the centromere-specific nucleosomes remain to be completely understood. We construct a homology model of the Saccharomyces cerevisiae centromeric nucleosome and generate a biophysically-principled C-loop model for elongation of Saccharomyces cerevisiae kinetochore. We present simulation automation techniques by means of two web-based servers: iFold (http://iFold.dokhlab.org) and iFoldRNA (http://iFoldRNA.dokhlab.org). iFold enables automated simulations of protein folding, unfolding using discrete molecular dynamics. iFoldRNA enables ab initio RNA structure prediction using replica-exchange discrete molecular dynamics simulations. We also demonstrate rapid and accurate three-dimensional structure prediction of over 150 RNA molecules. We used all-atom molecular dynamics simulations to study the mechanistic and structural differences between two anticancer therapeutics - cisplatin and oxaliplatin. Our simulations suggest that the cisplatinated- and oxaliplatinated- DNA cause differential effects on the dynamics and bending propensities of adducted DNA. This study suggest a role of differential bending propensities in the efficacies of oxaliplatin and cisplatin. In summary, the research presented in this dissertation helps us understand the mechanisms of biomolecular interactions at atomic and mesoscale levels. This dissertation adds to scientific knowledge by a set of methodologies for exploring the dynamics of protein and RNA molecules. Physically-principled simulations of the nucleosome core particle yield experimentally-testable hypotheses on chromatin structure and function.