Cameron F. Abrams
Professor, Chemical and Biological Engineering
Professor (by courtesy), Drexel University College of Medicine,
Department of Biochemistry and Molecular Biology
Drexel University

Hosted by Jim Pfaendtner

Understanding and Harnessing Biomolecular Metastabilities

The induced-fit hypothesis of Koshland and the conformational-selection hypothesis of Changeux in the 1950’s and 60’s marked major leaps forward in our understanding of biomolecular function.  Then radical, the now well-accepted idea behind these hypotheses is that proteins and other biomolecules switch among long-lived, functionally relevant conformational states, the populations of which are influenced by intermolecular interactions.  But it takes more than acceptance of an idea to apply it successfully, and we all too often lack an understanding of conformational metastabilities precise enough for the design of either pharmaceuticals or industrially useful mutants.  In the first part of this talk, I’ll describe how we use computational methods based on all-atom molecular dynamics (MD) to pursue this understanding.  Two methods of particular emphasis are temperature-accelerated molecular dynamics for exploring large-scale conformational changes and the string method in collective variables for measuring conformational statistics.  These methods have provided an unprecedentedly detailed view of conformational metastabilities in several systems, including β2-microglobulin, the protein responsible for dialysis-related amyloidosis; the insulin-receptor kinase domain; and flavoprotein oxidases essential for aerobic biology.  In the second part of this talk, I’ll discuss application of a theory of the hierarchical metastability of the human immunodeficiency virus (HIV) toward the development of anti-AIDS microbicides.  This theory posits that high internal pressure imparts stress to the bilayer envelope of the virus, bringing it close to a stability limit localized at the transmembrane domains of its surface spikes, which themselves are held in a metastable state from which decay to a ground state executes the virus’ cellular-entry programming. Agents we have designed with dual-binding-site specificity to HIV have recently been shown at nanomolar concentrations to trigger this metastability, leading to sudden and irreversible lysis of the virus.  We are in the early stages of using molecular simulations to understand the details of this behavior, with a long-term goal of the development of commercially viable anti-AIDS microbicides.  The talk will conclude with a molecular-simulation outlook on the calculation of fluxes connecting metastable states.