Theoretical Molecular Biophysics is an interdisciplinary research field at the interface between physics, computational chemistry, and structural biology. We focus on understanding general physical chemical principles of membrane protein function. We develop and apply tools for the efficient analyses of dynamic hydrogen-bond networks in complex bio-systems.  To enable accurate numerical simulations of bio-systems that contain cofactor molecules, we derive force-field parameters.

Our research directions are as follows:

Protein folding: the bacterial Sec protein secretion machinery

The Sec protein secretion machinery is essential for the bio-synthesis of proteins in bacteria. Key components of this pathway are the soluble SecA protein motor and the membrane-embedded SecY protein translocon. Theoretical biophysics techniques can provide an atomic-detail movie of the protein translocase in action. We used numerical simulations to characterize the dynamics of SecA, and constructed two-dimensional hydrogen-bond maps that alowed us to identify a cluster of dynamic hydrogen bonds potentially important for long-distance conformational coupling in SecA. We derived a model of SecA bound to a secretory protein fragment; this model provides the foundation for future quantum mechanical computations of the ATP-hydrolysis reaction.

Protonation-coupled protein and water dynamics

Proton transfer is a chemical reaction of fundamental importance for biology. Examples of bio-systems whose functioning involves proton transfers include photosystem II, the protein/cofactor machinery that splits waters, ATP synthase, or the gastric proton pump. Key open questions include how changes in the protonation state couple to the protein and water dynamics, and how protons are transferred across long distances. Computer simulations allow us to study the protein motions and compute reaction pathways for proton transfer, and thus characterize the mechanism of proton transfer.

We have implemented algorithms that allow us to identify and characterize protein/water hydrogen-bond networks with potential role in proton transfer and transient proton storage, and used these algorithms to study dynamic hydrogen bond networks of photosystem II.

Biomembranes and membrane reactions

Lipid membranes surrounding biological cells host proteins that catalyze chemical reactions important for cell physiology. The theoretical biophysics approach, with which can study protein motions in hydrated lipid membrane environments, provides valuable tools to dissect mechanisms by which the lipid bilayer composition impacts protein binding and protein function. We are particularly interested in membrane-embedded proteins whose functioning couples to the lipid membrane, including via sensing of the membrane lateral pressure.