Biomolecular Modeling: Nucleic acids structure and function
Our current research topics include DNA repair and fidelity mechanisms, chromatin folding, and RNA structure and function. To tackle these challenging problems, we are developing innovative molecular modeling, bioinformatics, and mathematical methods and collaborating on the applications with experimental groups.
DNA repair and fidelity mechanisms DNA polymerases are essential for the maintenance of genome stability during DNA replication and repair. They orchestrate the addition of new nucleotides to a growing chain of DNA by catalyzing a nucleotidyl transfer reaction which increases the primer strand by one base pair. Since malfunction of DNA polymerases can lead to various cancers and premature aging, it is important to understand polymerase mechanisms at the atomic level. Our aim is to delineate both the conformational and chemical-pathway aspects in polymerase catalytic cycles for various DNA polymerase families to unravel their selectivity and fidelity properties. We have used molecular dynamics, quantum/molecular mechanics (QM/MM), and transition path sampling methods, and other novel sampling tools to elucidate the atomic-level details of how polymerases work in the cell. Our current goal is to establish the key geometric/energetic/dynamic selection criteria for polymerases using modeling and simulation protocols for large-scale, long-time conformational and chemical pathways in collaboration with experimentalists.
Chromatin folding Fundamental genome packaging and regulatory processes in eukaryotes are determined by the structure of and interactions within the chromatin fiber – the nucleoprotein complex consisting of tightly packed nucleosome units connected by linker DNAs, much like yarn wrapped around many spools. Indeed, how chromatin, and hence transcription regulation, works is ultimately a structural problem. Our long-term research goal is to integrate structural and dynamical aspects of chromatin organization to delineate the mechanisms of transcriptional regulation mediated through protein factors, epigenetic marks, and environmental conditions. Our group has developed increasingly refined mesoscale models to simulate chromatin dynamics and predict chromatin’s internal organization. Our current research topics include developing rigorous methods to treat chromatin electrostatics and investigating the roles of DNA linker length, histone variants, chemical modifications of histone tails, and remodeling proteins in chromatin folding.
RNA structure and function Biological and synthetic RNAs perform a broad range of functions. Small regulatory RNAs like microRNAs, for example, can control the expression of many proteins. In addition, synthetic RNAs developed from in vitro selection – an experimental technique for identifying active RNAs from random sequence pools – have led to many ligand-binding and catalytic RNAs. These advances in RNA highlight the versatility of RNA molecules. Indeed, RNAs have been engineered for application as biosensors, therapeutic agents, and molecular tools for synthetic biology and nanotechnology. Our modeling of RNA structure and function aims to discover novel active RNA molecules via analysis, folding and design of RNA sequences and structures. In RNA analysis, our group has contributed to RNA graphical representations to describe RNA’s structural repertoire and applied bioinformatics tools to identify RNA’s tertiary interaction motifs. We are currently developing computational methods for modeling key aspects of in vitro selection technology (generating, analyzing and designing large sequence pools) to guide and improve identification of novel active RNAs. We are also using rational design methods to engineer RNAs as tools for probing biological processes (e.g., transcription).