Modeling the Biophysics of Cellular Membranes
- Alexander J. Sodt,
PhD, Head, Unit on Membrane Chemical Physics - Andrew Beaven, PhD, Postdoctoral Fellow
- Amirali Hossein, PhD, Postdoctoral Fellow
- Laura Lopes, PhD, Postdoctoral Fellow
- Kayla Sapp, PhD, Postdoctoral Fellow
- Jay Dadhania, BS, Postbaccalaureate Fellow
- Noah Englander, BS, Postbaccalaureate Fellow
- Noah Feng, BS, Postbaccalaureate Fellow
- Benjamin Hu, MS, Postbaccalaureate Fellow

The integrity of lipid membranes is essential for life. They provide spatial separation of the chemical contents of the cell and thus make possible the electrical and chemical potential differences that are used to transmit signals and perform work. However, the membrane must be broken frequently to form, for example, new membrane structures in the cell. The simplest structure is a vesicle to transport cargo. Such vesicles are constantly cycled between organelles and the outer plasma membrane. Thus, there is a careful balance between boundary-establishing membrane fidelity and the necessary ability of the cell to change these boundaries.
The challenge in studying the membrane is its complexity. The membrane is a thin sheet of small molecules, i.e., lipids. There are hundreds of types of lipids in the cell. Each lipid changes the properties of the membrane in its vicinity, sometimes making the sheet stiffer, sometimes softer, and sometimes acting to bend the membrane into a ball or tube. Furthermore, the lipids are constantly jostling and tangling, both with each other and with proteins embedded in the membrane. To predict of how membranes are reshaped thus requires not only knowing how lipids affect the properties of the membrane surface, but also the location of specific lipids.
The question as to how molecular-scale features influence extensive biological processes must be answered in the language of physical laws. Physics is the language of mechanism at the molecular scale. The challenge is linking physics to the ‘big’ processes that happen in life. Our lab uses detailed physics-driven molecular simulation to ‘build up’ models that can be applied at the much larger level of the cell, which requires retaining important information and eliminating irrelevant details. The software our lab develops is based on the models that we are building. Thus, a broad objective of our research is to create a publicly available software package that can be used either as a stand-alone application for analyzing membrane-reshaping processes or as a library for cellular-scale modeling packages for which the role of the membrane may be unclear or unanticipated.
Another key component of our research is to seek the best possible validation of our models. Few techniques are able to yield molecular information about lipids. Recent breakthroughs that break the diffraction-limit barrier are typically only applicable to static structures much larger than a molecular dye. In contrast, lipids are small and dynamic. Our group is making a sustained effort to validate our simulation findings by applying neutron scattering techniques. This year, our lab initiated new collaborations on the basis of our previous years' work developing methodology for predicting the scattering signal from our simulations.
The projects use the NIH computing resources, including the Biowulf cluster, to run simulations and models. We use molecular dynamics software (such as NAMD and CHARMM) to conduct molecular simulations. In-house software development for public distribution is a key element of the lab's work.
How lipid composition determines the stiffness of biological membranes.
Cellular membranes are the medium by which cellular protein machinery is transported to and from the plasma membrane. Patches of membrane are constantly reshaped by the cell into spherical transport vesicles. The stiffness of cellular membranes is a key property that determines the work the cell must expend to reform the membrane in order to maintain cellular health. In this work, we derived a new formula that relates the variance in lipid composition to stiffness of the membrane. The formula opens a new research direction into understanding why we have the lipids we have: that the cell uses variations in lipid's sensitivity to the membrane shape to make the surface both easy to deform and hard to break. Along with the formula, Reference 3 presents simulations of simple binary mixtures of lipids with complex interactions to validate the softening effect of lipid dynamics.
Lipidome adaptation at high pressure provides clues as to why we have the lipids we have.
In our collaboration with the Budin lab, we analyze an unusual organism to provide evidence that our lipidomes are designed to facilitate transport within the cell, and that it is not just the work of protein machinery [Reference 2]. By comparing the lipidomes of deep-sea comb jellies with their shallow relatives, we established that a particular set of lipids (plasmalogens) are enriched at high pressure. Simulations and biophysical experiments further confirmed that a particular property of the lipidome is maintained as pressure is increased, i.e., its ability to support unusual membrane shapes that are necessary for traffic within and out of the cell.
Dynamic protein-lipid interactions affect function.
Two studies use molecular simulations to relate membrane-protein interactions to biological function. With the Hess lab, simulations of a virus’s protein interacting with a special signaling lipid (“PIP2”) suggest how this highly charged lipid leads to clustering of viral proteins at the plasma membrane [Reference 1]. With the Randazzo and Byrd labs, simulations indicate how structural features of an amphipathic helix determine the conformation of a critical signaling protein [Reference 5].
Publications
- Conserved sequence features in intracellular domains of viral spike proteins. Virology 2024 599:110198
- Homeocurvature adaptation of phospholipids to pressure in deep-sea invertebrates. Science 2024 384:6703
- Softening in two-component lipid mixtures by spontaneous curvature variance. J Phys Chem B 2024 6:6317–6326
- Biomimetic vesicles with designer phospholipids can sense environmental redox cues. JACS Au 2024 4:1841–1853
- Point mutations in Arf1 reveal cooperative effects of the N-terminal extension and myristate for GTPase-activating protein catalytic activity. PLoS One 2024 19:e0295103
Collaborators
- Itay Budin, PhD, University of California San Diego, La Jolla, CA
- Andrew Byrd, PhD, Center for Structural Biology, NCI, Bethesda, MD
- Samuel T. Hess, PhD, University of Maine, Orono, ME
- Enver C. Izgu, PhD, Rutgers, The State University of New Jersey, New Brunswick, NJ
- Paul Randazzo, MD, PhD, Laboratory of Cellular and Molecular Biology, Center for Cancer Research, NCI, Bethesda, MD
- Olivier Soubias, PhD, Structural Biophysics Laboratory, Center for Cancer Research, NCI, Frederick, MD
Contact
For more information, email alexander.sodt@nih.gov or visit https://www.nichd.nih.gov/research/atNICHD/Investigators/sodt.