Modeling the Biophysics of the Membrane
- Alexander J. Sodt, PhD, Head, Unit on Membrane Chemical Physics
- Victor Chernomordik, PhD, Volunteer
- Christina M. Freeman, BS, Postbaccalaureate Fellow
- Julia Rakas, Summer Student
- Maya Wilson, Summer Student
Mechanisms of protein function are determined at the molecular level. For example, a G protein–coupled receptor (GPCR) binds to a drug or signaling molecule, and the shape of the protein is modified (a new conformation). The conformation is sensed inside the cell. The molecular movements are on the sub-nanometer scale, 10 billion times smaller than a meter. Such molecular events can then trigger changes in the cell at a scale one hundred thousand times larger. The whole process requires a complex coordination of many such events.
The goal of models and simulation is to be the computational extension of knowledge in the field of molecular biology. The models incorporate not only laboratory observations but also bottom-up molecular physics. The ultimate goal is to make predictions of how external factors (such as disease) affect a biological function and to help develop potential cures that consider, for example, side effects that may be unanticipated by attempting to target a single protein. A more modest goal is to identify missing pieces of a biological puzzle where, for example, our collective knowledge and intuition are inconsistent with observations.
The piece of the puzzle studied in this lab is the role of the lipid membrane of the cell. The membrane deserves independent study because of its essential role in signaling. It is the chemical and informational barrier between the cell and organism, as well as between intracellular compartments. It must be reshaped and transformed during, for example, neurological function, formation of cellular organelles and vesicles, or the viral replication cycle. Along with the cytoskeleton, it is the major structural element that gives a cell its form.
A broad objective is to create a publicly available software package that can be either used as a stand-alone application for analyzing membrane-reshaping processes or as a library for cellular-scale modeling packages where the role of the membrane may be unclear or unanticipated. The model will incorporate the physical mechanisms we are investigating in the narrower objectives of the lab. These include: the influence of lipid curvature stress on the conformation of a protein; whether through-bilayer coupling can amplify a signaling state (for example, of a GPCR); and whether protein motifs (e.g., a thick hydrophobic region of a protein) can enhance the local lipid composition around a protein. These projects will address how the lipid micro-environment is controlled by the cell to change coupling between protein signaling states.
The purpose of the ongoing projects of the Unit is 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. The project is then 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's work.
Effect of protein palmitoylation on curvature stress
Enveloped viruses bud off the cell, incorporating the plasma membrane into their envelope. Preliminary 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 will be tested in simulation by examining the curvature effect of free palmitic acid (using techniques refined in Dr. Sodt's post-doctoral work) and comparing the effect with palmitoylation of peptide motifs.
Theory of the Hofmeister effect on membrane material properties
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. The lab is generally interested in how the chemistry of the elements of the membrane affect bilayer properties, and a surfactant-laden interface between oil and water is a simple model of the leaflet surface.
First, we are developing a theoretical model for how surface-bound ions affect the material properties of the bilayer, e.g., stiffness. This can be verified by simulations of a bilayer conducted in the presence of a series of, for example, halide anions. It is expected that the larger iodine ion is able to permeate the bilayer more than the smaller halides, which would lead to a change in the chemical interactions at the surface, and thus, its material properties. The model is being used by the Bezrukov lab to interpret the effect of Hofmeister anions on the function of ion channels.
Development of software and models to characterize lipid-protein interactions
A software package is being developed to compute the effect of membrane deformations between two or more proteins in close proximity. The “continuum” model will be used to help explain cooperative effects between rhodopsin proteins observed in the lab of Klaus Gawrisch. We are validating the model and software in part by conducting molecular simulations of rhodopsin states and comparing the predicted deformations between the molecular and continuum models.
Publications
- Sodt A, Venable R, Lyman E, Pastor R. Nonadditive compositional curvature energetics of lipid bilayers. Phys Rev Lett 2016;117:138104.
Collaborators
- Sergey Bezrukov, PhD, Section on Molecular Transport, NICHD, Bethesda, MD
- Klaus Gawrisch, PhD, Laboratory of Membrane Biochemistry and Biophysics, NIAAA, Bethesda, MD
- Edward Lyman, PhD, University of Delaware, Newark, DE
- Joshua Zimmerberg, MD, PhD, Section on Cellular and Membrane Biophysics, NICHD, Bethesda, MD
Contact
For more information, email alexander.sodt@nih.gov or visit http://sodtlab.nichd.nih.gov.
