Modeling Cellular Membranes and Associated Proteins with Improved Force Fields

The research in my laboratory focuses on cellular membranes and associated proteins that have a wide range of importance in human health from controlling import/export of drugs, trafficking within the cell, autoimmune disorders attacking the membrane structures and promoting cellular growth. Since we focus on using molecular simulations, the key precise modelling of membranes and associated proteins is the development of accurate descriptions of how biological molecules interact, known as a force field (FF). My lab has focused on improving the lipid FF toward a highly diverse set of lipids to represent cellular membranes, but additional efforts are needed to update this for more accurate approaches, i.e., full inclusion of long-range dispersion interactions and methods to include polarization effects that are extremely important for the varied environment a membrane contains (charged, polar and non-polar regions). Some key examples where improvements are needed are anionic lipids and sphingolipids where recent experimental data demonstrate that our lipid-lipid interactions are too strong. We will also focus on improving FF parameters for peptide-lipid interactions. All FF development will involve new wet lab data on lipid monolayers and isothermal titration calorimetry to aid in FF adjustment. Ultimately, improved FF parameters will result in increased accuracy of our simulations models but are open source to allow the wider community to explore topics of specific interest to their labs. A core thrust in our lab has also been developing accurate cell membrane models from single-celled organisms to organelles within human cells. We will focus on developing more extensive models for the various organelles of yeast that will be used in our simulations of intracellular lipid transport with a class of proteins that forms membrane contact sites (MCSs). We will continue our efforts with the oxysterol-binding homolog protein 4 (Osh4) of yeast as a model for intracellular lipid transport focusing on how this protein can exchange lipids between two organelles. In addition, we plan to extend this work to a similar protein in humans, ORP3, to focus on the fundamental mechanisms these class of proteins use to transport lipids and form MCSs. This will involve computational modeling and collaborations to obtain structures of these proteins at the MCS. Our final area of research will be on proteins that have single-pass transmembrane (TM) helices with a focus on plexinA1 that forms homodimers for proper function. Studies on plexinA1 will initially focus on modeling how it forms stable homodimers towards understanding its importance in remyelination for multiple sclerosis to growth in certain cancers. Computational predictions will be validated with wet lab assays. Then, we will investigate inhibitory peptides for homodimerization and use molecular simulations and wet lab assays to train a machine learning model to predict improved inhibitory peptide sequences for potential drug design. Project Number: 1R35GM161807-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Jeffery Klauda | Institution: UNIV OF MARYLAND, COLLEGE PARK, COLLEGE PARK, MD | Award Amount: $405,390 | Activity Code: R35 | Study Section: Maximizing Investigators' Research Award - E Study Section[MRAE] View on NIH RePORTER: https://reporter.nih.gov/project-details/11260650