In living cells, proteins fold, bind ligands and undergo ligand-induced changes that result in signal transduction. We use computational (molecular dynamics and bioinformatics) methods to understand the structural, energetical and dynamical aspects of these events and to facilitate controlled modifications of signal transduction for therapeutical applications.

Folding: Restriction endonucleases [REBASE] are extremely important molecular biology tools. They present an interesting case study for protein folding, because they share structural similarity despite sequence dissimilarity. In collaboration with the labs of Rich Roberts, Aneel Aggarwal and Harold Scheraga, we study protein folding and physico-chemical properties and mechanisms that enable restriction endonucleases to fold into functional structures. The available structures of Type II REases were analyzed (M.Y . Niv, D.R. Ripoll, J.A. Vila, A. Liwo, E. S. Vanamee, A. K. Aggarwal, H. Weinstein and H. A. Scheraga, accepted in NAR) The REases were grouped according to the connectivity of the core secondary-structure elements. The aligned core substructures are available here.

Protein/protein and protein/peptide interactions: We are interested in protein/peptide interactions specificity and modulation of molecular interactions by posttranslational modifications such as phosphorylation. PDZ domains are scaffolding domains involved in numerous cellular processes via interaction with C-terminal peptides [PDZBase]. Recently we developed a flexible docking and scoring procedure, applicable not only to experimental structures, but also to homology models of PDZ domains.

Ligand-induced activation: Active states of G-protein coupled receptors (GPCRs) are relevant for study of agonist binding and drug design. Recently it has been suggested that GPCRs may have several active states, elicited by different ligands and resulting in activation of different signaling pathways (eg T. Kenakin, Trends in Pharmacol. Sci. 2003). We use the conformational changes occurring in Rhodopsin upon ligand binding (deduced from disulfide cross-linking, spin-labeling, NMR and fluorescence experiments) to build activated models of Rhodopsin and other GPCRs. The constraints (summarized here http://physiology.med.cornell.edu/GPCRactivation/gpcrindex.html) were incorporated in a CHARMM-based procedure to obtain templates for the active conformations of GPCRs (JCAMD 2006 Jul-Aug;20(7-8):437-48).