Molecular Mechanisms in Membrane Bioenergetics, Transport and Signaling

National Heart, Lung, And Blood Institute

Investigators

Linked publications & trials

Abstract

AREA 1. MECHANISMS AND ORGANIZATION OF MEMBRANE PROTEINS A major focus in Area 1 has been to further our understanding of the mechanisms that control the permeation of ions cross protein channels. Our studies of the human lysosomal channel TMEM175, which is implicated in Parkinson's disease, revealed a novel mechanism of ion specificity that stems from subtle but consequential differentials in the degree of dehydration among different ions competing for passage through the channel. Our studies of Shaker, a prototypical channel in eukaryotic neuronal physiology, contributed to uncover the structural mechanism that underlies a process known as C-type inactivation - which controls the temporal resolution of the ionic currents facilitated by this and similar channels. In parallel to this research, we have continued our investigations of the factors that explain the mechanism and specificity of bacterial membrane transport systems that contribute to the phenomenon of multidrug resistance; and of an important class of human membrane-bound enzymes, known as DHHC, whose role is to catalyze a physiologically crucial post-translation modification known as palmitoylation. AREA 2. DEVELOPMENT OF MOLECULAR SIMULATION METHODS In Area 2 we have continued our efforts to development and disseminate novel molecular-simulation methodologies with which to examine the mechanisms of membrane proteins as well as the factors that control their membrane organization and regulatory interactions with the lipid bilayer. In this past year our central achievement this area has been a new analysis methodology to derive free-energy landscapes from simulation data obtain with enhanced-sampling techniques. In addition, we have continued a long-standing effort to formulate methodologies to integrate experimental and simulation data. The specific focus in the past year has been on the technique known as hydrogen-deuterium exchange (HDX).