Understanding Protein Folding and Assembly with Molecular Simulations and Information Theory

Prof. Scott Shell

University of California Santa Barbara, Chemical Engineering

Date: October 25, 2012

Time: 4:00 p.m.

Location: Engr II Rm 1519

Peptides have emerged as versatile self-assembling systems that hold promise as controllable, energy efficient, environmentally benign alternatives for nanoscale materials and scaffolds. Rational peptide engineering strategies demand a deep understanding of the molecular driving forces underlying self-assembly, yet it remains an immense challenge to predict even basic self-assembly properties, such as what nanostructure a given peptide will form (e.g., fibrils vs. nanotubes vs. spheres). This problem is particularly challenging due to the delicate balance different driving forces (e.g., hydrophobic interactions, hydrogen bonding, electrostatics) that often magnifies tiny sequence changes into dramatic self-assembly effects.

Here, we discuss how novel molecular simulation methods can provide insights into the origins or sequence-specific self-assembly behavior. Using all-atom simulations with enhanced-sampling techniques, we show that computed free energies of small oligomer formation suggest several mechanisms by which the balance of hydrophobic and electrostatic interactions can lead to unexpected assembly propensities, including through unexpected but strong entropic forces. To reach larger assembly scales, we describe a powerful new coarse-graining theory that permits systematic development of simpler models from these all-atom calculations. These coarse-grained models are then deployed in larger-scale simulations and suggest distinct mechanisms of self-assembly in a variety of different systems.

Prof. M. Scott Shell joined the Chemical Engineering Department at UC Santa Barbara in 2007. His group develops novel molecular simulation, multiscale modeling, and statistical thermodynamic approaches to address several problems in contemporary biophysics and condensed matter theory, including folding and design principles in proteins; peptide structure, self-assembly, and aggregation; and water and aqueous solutions. Prof. Shell earned his B.S. in Chemical Engineering at Carnegie Mellon in 2000 and his Ph.D. in Chemical Engineering from Princeton in 2005, followed by postdoctoral work at UC San Francisco in the Department of Pharmaceutical Chemistry. He is the recipient of a Dreyfus Foundation New Faculty Award (2007), an NSF CAREER Award (2009), a Hellman Family Faculty Fellowship (2010), a Northrop-Grumman Teaching Award (2011), and a Sloan Research Fellowship (2012).