The purpose of this project was to investigate the physical mechanisms by which the lipid membrane influences the protein function that underlies most biological processes. A typical project in the lab identifies a hypothesis for a particular mechanism in conceptual terms, forms a mathematical or physical model for the process, then tests and refines the model using a molecular simulation. Next the project is developed to make predictions that can be tested in the laboratory. The projects use the NIH Biowulf computing cluster to run the simulations and models. Molecular dynamics software (such as NAMD and CHARMM) are used to conduct molecular simulations. In-house software development for eventual public distribution is a key element of the lab. A number of preliminary results have been developed this year. 1) Enveloped viruses bud off the cell, incorporating the plasma membrane into their envelope. Experiments from the Zimmerberg lab showed that palmitoylation of the HA influenza protein reduces the size of viral-like particles (VLP). A model for this effect is that palmitoylation affects the lateral stress of the budded membrane, stabilizing high curvature. This was tested in simulation by examining the curvature effect of free palmitic acid (using techniques refined in Dr. Sodts post-doctoral work), and demonstrating that the effect was equivalent if the palmitic acid is part of a peptide motif. The results qualitatively explain the observed reduction in size of the VLP. 2) A software package was developed to compute the effect of membrane deformations between two or more proteins in close proximity. The continuum model will be used to explain cooperative effects between rhodopsin proteins observed in the lab of Dr. Gawrisch of NIAAA. The model and software was validated in part by conducting molecular simulations of rhodopsin states, and comparing the predicted deformations between the molecular and continuum models. 3) The Hofmeister effect is broadly understood to be a change in the effective surface tension between water and oily substances as a result of charged ions. First, a theoretical model was developed for how surface bound ions will affect the material properties of the bilayer, e.g., stiffness. Then, simulations of a bilayer were conducted in the presence of a series of halide (F to I) anions. As expected, the larger iodine ion was observed to permeate the bilayer more than the smaller halides. The model is being used by the Bezrukov lab at the NICHD to interpret the effect of Hofmeister anions on the function of ion channels.
