CAREER: Critical Issues for Biomolecular Simulations: Organic Solvents, Protein-Protein and Nucleotide-Protein Interactions

North Carolina State University, Raleigh NC

Investigators

Abstract

This CAREER award supports research and education in computational biophysics. Research activities will focus on biomolecular applications, and build on methodological advances made by the PI in the treatment of long-range electrostatic interactions between biomolecules, as well as new multiscale developments. Specific research goals focus primarily on aspects of nucleic acid recognition, and on protein-protein interactions as they occur in the Ras superfamily of GTPases. Crucial cell processes such as DNA replication, repair and transcription, mRNA translation, viral RNA insertion, etc., all involve complex interactions between proteins and nucleic acids. A true, physics-based characterization of these interactions has remained elusive, because of their relatively small magnitude and their varied physical origins. These interactions determine the "recognition" contacts between molecules, which allow for site-specific binding proteins to choose the correct nucleic acid sequence from millions of possibilities. Similar concepts of complexity and technical difficulty apply to protein-protein interactions. As a particular model for investigation with large-scale biomolecular simulations, the PI has chosen the family of GTPases, which act as molecular switches involved in signal transduction cascades and motility in mammalian cells. Additionally, the PI will also investigate the properties of selected organic solvents for the determination of protein surface binding sites. Experimentally, it has been established that the structure of many proteins solvated in a variety of organic solvents is almost identical to that in an aqueous environment. So, organic solvents allow experimentalists to probe the binding sites of proteins via the multiple solvent crystal structure (MSCS) method. Currently, there is little theoretical understanding of the properties of proteins solvated with organic molecules, which therefore represents an important opportunity for research. The PI plans to carry out these investigations in consultation and collaboration with other researchers at NC State and at a local NIH laboratory. The PI will focus on teaching two courses that showcase the power of biomolecular simulations and the applications outlined under this CAREER proposal. These courses aim to satisfy local needs for a survey course on atomistic simulation methods and an intense "short-course" on biomolecular simulations. These courses will form part of the educational effort of the Center for High Performance Supercomputing (CHiPS). Plans to recruit students from underrepresented groups, especially women and hispanics, and to participate in international collaborations are integrated into research and education activities. Broader impacts: The research component impacts the fields of quantitative biology as well as theoretical and computational materials research. The education component supports a computationally able 21st century workforce and provides opportunities for members of underrepresented groups. %%% This CAREER award supports an integrated research and education plan in the area of Computational Biophysics. Based on recent algorithmic advances combined with the growing power of parallel computing, it is now becoming possible to directly investigate the action of biomolecules with the power of molecular dynamics simulations. The PI's research will primarily focus on: (i) organic solvents for the determination of protein surface properties; (ii) DNA sequence-dependent structure in solution; (iii) protein-protein interactions as they occur in the Ras superfamily of GTPases. The investigations of these systems will all represent an important step in enhancing our understanding of fundamental biomolecular processes. The educational goals of this CAREER proposal, are based on the concept of a "multiscale" education for graduate students which is to take place under the auspices of a newly developed Center aimed at fostering high performance supercomputing, i.e., an education that ensures that students have a broad set of computational simulation skills at their disposal, rather than being focused on a narrow field. To this end, the PI - who is an active member of the Center-will develop a survey course on atomistic simulation methods and develop important "short courses" on biomolecular simulation methods. These courses will provide specific venues for integrating and highlighting the research efforts of the PI with the educational effort. In addition, the PI aims to work on recruiting underrepresented students into the research group, with a particular focus on women and hispanics. Fully recognizing the importance of international collaborations for both research and education, the PI is currently involved in two separate initiatives to set up a foreign exchange program - one with the TU-Berlin and one with Argentina. Broader impacts: The research component impacts the fields of quantitative biology as well as theoretical and computational materials research. The education component supports a computationally savvy 21st century workforce and provides opportunities for members of underrepresented groups. *** 123456789012345678901234567890123456789012345678901234567890123456789012