Molecular Mechanisms in Membrane Bioenergetics, Transport and Signaling

National Heart, Lung, And Blood Institute

Investigators

Linked publications, trials & patents

Abstract

AREA 1. MECHANISMS AND ORGANIZATION OF MEMBRANE PROTEINS A major focus in Area 1 has been to further our understanding of the interplay between membrane proteins and the surrounding lipid bilayer. Specifically, we investigated how the lipid bilayer contributes to processes of protein self-organization. At the single-molecule level, we studied in detail the dimerization of a membrane protein of the CLC family. This type of process, known as oligomerization, is observed for 70% of membrane proteins of known structure, but the driving factors remain unclear, and so our studies of CLC are broadly significant. On a larger scale, we also studied ATG9A, a membrane protein known to be crucial for the development of the autophagosome. Specifically, we examined how supramolecular arrays of this protein promote the formation of vesicles that ultimately serve as membrane seeding sites. These studies continue to substantiate our perspective that the local deformation of the bilayer caused by some membrane proteins can be thought of as an elemental step in a supramolecular, collective mechanism that ultimately defines the morphology of all cellular membranes, including those encompassing cellular organelles. In parallel to this research, we have continued our investigations of the factors that explain the specificity of membrane transport systems. In the past year we have completed two studies in this area: one focused on large class of bacterial transporters known to be key for the development of multidrug resistance; and another focused on an important class of transporters with an essential role in brain function, namely to help recycle neurotransmitters released during synaptic signaling. 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 first-of-its-kind methodology specifically designed to simulate changes in membrane morphology and quantify the associated energetic cost. A second focus in this area has been the improvement of biomolecular simulation forcefields. In the context of an ongoing study of the factors that explain the anion specificity of certain membrane channels and transporters, we calibrated and tested parameter sets for fluoride, chloride, bromide and iodide.