(5ar) Multiscale Modeling Studies of Self-Assembly in Biological Systems

Nguyen, H. D. - Presenter, University of California, Irvine
Brooks, III, C. L. - Presenter, The Scripps Research Institute

The common theme of my research experiences has been developing a comprehensive understanding of the basic physical principles that underlie the formation of ordered protein structures in various biological systems using different novel computer simulation techniques.

My graduate research, which was under the guidance of Prof. Carol K. Hall at North Carolina State University, focused on the development, refinement, and application of a protein model at intermediate resolution to examine the competition between protein folding and aggregation, especially the formation of ordered structures such as amyloid fibrils, which have been implicated in the pathology of several neurodegenerative diseases including Alzheimer's and Parkinson's. When coupled with discontinuous molecular dynamics, a fast alternative to standard molecular dynamics, our protein model, which contains enough genuine protein-like character to mimic real proteins, allowed us to simulate truly multi-peptide systems of polyalanines over relatively long time scales. To our knowledge, these were the first simulations to span the whole process of fibril formation from the random coil state to the fibril state on a large system. Therefore, we were able to examine the kinetics and thermodynamics of fibril formation in detail.

My postdoctoral research with Prof. Charles L. Brooks III in the Department of Molecular Biology at the Scripps Research Institute is aimed at developing multiscale models and simulation techniques for studying the self-assembly and maturation process of icosahedral viral capsids, which are the coats that protect the viral genome in the form of DNA or RNA. Icosahedral capsids are composed of multiples of 60 copies of individual capsid proteins that must assemble correctly, rapidly, and reproducibly on a biological timescale in order to propagate an infection in vivo. Once assembled, capsid proteins undergo a rearrangement process in which large-scale conformational changes take place to achieve their viral functionalities. Elucidating the self-assembly and stability of viral capsids may have the potential to assist in developing novel approaches to interfere with viral infection. In addition, gaining insights into the capsid self-assembly process may also aid our exploitation of beneficial applications of viral capsids in medicine and materials science. So far we have been able to decipher detailed kinetic mechanisms and thermodynamics of the self-assembly of empty viral capsids by performing molecular dynamics and rigid-body Monte Carlo simulations on large systems containing multiple capsid subunits with our newly-developed geometric models. Also, we have conducted structural studies to investigate assembly mechanisms using our newly-developed united-atom model and explored the initial stages of viral capsid assembly by using all-atom CHARMM. Finally, we have examined physical properties such as elastic behavior, capsid expansion and buckling transition of numerous viral capsids using the Normal Mode analysis technique and CHARMM.

As a faculty member, one of my main proposed research areas involves investigation of the self-assembly of biological and biomimetic nanoscale materials that are based on not only amino acids but also nucleic acids.