I. Structure, Folding and Functioning of Membrane Proteins: Our first project focuses on deciphering the molecular mechanism of pH-dependent refolding and membrane insertion of the diphtheria toxin T-domain (DTT), which is considered to be a paradigm for cell entry of other bacterial toxins (e.g., tetanus and botulinum) and has a potential for targeted delivery of anti-cancer therapies. Understanding the pH-triggered insertion of DTT will also reveal general physicochemical principles underlying membrane protein assembly and signaling on membrane interfaces. Previously, we identified key intermediate states along the insertion pathway, established the concept of conformational switching for DTT action, and developed new methodologies for structural, kinetic and thermodynamic characterization of membrane protein refolding/insertion. Our plans include bringing together molecular dynamics simulations and sophisticated spectroscopic experiments in order to understand molecular mechanisms of DTT membrane insertion. Other projects in the lab deal with structure-function relationships of ion-channel blockers, antimicrobial peptides and of the Bcl-2 family of proteins carrying out both pro-apoptotic and anti-apoptotic functions.