Research Interests



Dynamics of Ras proteins in solution and in membrane

K-Ras

Simulations have played a key role in elucidating the dynamics of Ras proteins in the aqueous and membrane environments (see our recent review on this topic). We apply classical and advanced molecular dynamics simulations on the isolated catalytic domain in water [e.g. 1], the lipid-anchor [e.g. 2] and the full-length Ras in bilayers of various lipid composition [3,4]. Our current focus is on K-Ras, which is the most frequently mutated Ras isoform in human cancers and developmental disorders. Ongoing projects revolve around the question of how somatic and genetic mutations may alter the population of conformational states and oligomerization behavior of K-Ras, and how these may affect interaction with effectors or modulators.



Organization of Ras proteins in membrane domains

Our work on membrane-organization of Ras proteins involves studying various lipid bilayer models using atomically detailed simulations [e.g. 1,2] and large-scale coarse-grained simulations of Ras-membrane complexes [3,4]. Previous simulations led to important insights into the physical basis for clustering and non-overlapping distribution of different Ras proteins in membrane domains. In particular, the nature of the lipid-modification was found to dictate the specific lateral organization of different Ras proteins on the membrane and that cholesterol modulates lipid domain stability and thereby the stability of Ras nanoclusters. Surface-bound proteo-oligomers can also be used to probe some of the mechanisms by which membrane curvature might be generated and/or maintained. However, a number of technical challenges remain to be solved in order to accurately and fully model oligomers of surface-bound Ras and other lipid-modified proteins [5], which is the object of our current focus.



Targeting an elusive foe

As part of a broader effort to developing anti-Ras therapeutics, we leverage insights emerging from the projects described above for the design of inhibitors that directly act on Ras. Our previous studies provided the initial clues about the allosteric nature of Ras and the role of conformational selection for its function [1,2,3,4,5,6]. This led us to contemplate the potential druggability of Ras at the time when this was thought hopeless [7]. Spurred in part by findings from large-scale genomic studies that the KRAS gene remains to be the main culprit in many forms of cancer, Ras is now back in the forefront of the search for new anti-cancer therapeutics. Our contribution to this effort includes the identification of novel allosteric ligand binding sites and prediction of small-molecule ligands that might bind to these sites [8,9]. Moreover, working with cell biologists and pharmacologists, we showed for the first time that nucleotide exchange factors are required for oncogenic Ras signaling and inhibiting nucleotide exchange is a valid approach to abrogating the function of oncogenic mutant Ras [9]. Our current effort in the search for isoform-selective Ras inhibitors includes developing methods to incorporate membrane into our dynamics-guided, ensembled-based drug-design scheme.


Interaction of NSAIDs with micelles and bilayers

We would like to understand the physical basis for the ability of common non-steroidal anti-inflamatory drugs (NSAIDs), such as aspirin, to cause gastrointestinal injury through their detrimental effect on surface membranes. This effect appears to be exacerbated by bile salts and reduced or eliminated by conjugating NSAIDs with phosphatidylcholines (PCs). We study the surface behavior, morphology and size of micellar particles that appear during simulations of binary and ternary mixtures of NSAIDs and bile salts with different PCs. Initial results suggest that NSAIDs can form potentially cytotoxic aggregates with bile acids, and may alter the normal physiologic balance between bile acids and PCs [e.g.1,2].