Membrane protein function is regulated by changes in the lipid composition of the host bilayer. This regulation, though well-established, remains enigmatic as evident by the many terms that are used to describe its mechanistic basis: changes in bilayer fluidity;changes in bilayer compression or curvature frustration energies, which can be combined into the bilayer deformation energy;changes in lateral pressure profile or lipid packing stress;changes in bilayer free volume;changes in bilayer stiffness. Changes in bilayer fluidity cannot be a major mechanism, as they cannot account for changes in the equilibrium distribution among different protein conformations. The remaining descriptors represent different approaches to parameterize the interactions among bilayer-forming lipids and between the lipids and the embedded proteins. The objective of the proposed studies is to develop an energetic framework for describing the functional consequences of the hydrophobic coupling between membrane-spanning proteins and their host bilayer, and to evaluate how membrane protein-bilayer interactions can be manipulated pharmacologically. The project is based on the notion of an elastic bilayer, in which membrane proteins undergo conformational changes that perturb the adjacent bilayer. This perturbation incurs an energetic cost that contributes to the overall free energy difference of the protein conformational changes. The protein-bilayer hydrophobic coupling therefore causes protein function to vary with changes in lipid bilayer material properties (thickness, lipid intrinsic curvature and the bilayer elastic compression and bending moduli), and the lipid bilayer becomes an allosteric regulator of membrane protein function. Changes in bilayer elastic properties can be characterized in terms of a restoring force that pulls on the embedded channel to minimize the bilayer deformation energy. Changes in this force can be measured using bilayer-embedded for transducers. The experiments will address the following questions. How good is the elastic bilayer model in predicting the energetic cost of channel-bilayer bilayer interactions? Can it be applied to multi-component lipid bilayers? This will be examined using phospholipids (alone or in combination), which form bilayers that differ in thickness and lipid intrinsic curvature. How do small amphiphiles, such as free fatty acids, antimicrobial peptides and other membrane-active molecules alter lipid bilayer material properties and membrane protein function? This will be examined by probing how selected drugs alter bilayer properties, and relating this information to more complex systems. Can PI(4,5)P2 (and other phosphoinositides) alter membrane protein function through local changes in bilayer material properties? This will be examined using gramicidin analogues with appropriately designed phosphoinositide-binding domains. Can the channel-bilayer hydrophobic mismatch drive a lateral association between bilayer-spanning channels? This will be studied by examining the relative stabilization of double- barreled channels of different lengths imbedded in bilayers of different thicknesses.

Public Health Relevance

The proposed studies will examine how important molecules, such as poly-unsaturated fatty acids (PUFAs), alter lipid bilayer properties and thereby membrane protein function. The experimental approach is based on the notion of an elastic bilayer, which contributes to the regulation of membrane protein function through hydrophobic coupling to the embedded membrane proteins. The bilayer elasticity can be altered by the adsorption of PUFAs and other membrane-active compounds, which provides a mechanistic basis for the changes in membrane protein function.

National Institute of Health (NIH)
Research Project (R01)
Project #
Application #
Study Section
Biophysics of Neural Systems Study Section (BPNS)
Program Officer
Chin, Jean
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Weill Medical College of Cornell University
Schools of Medicine
New York
United States
Zip Code
Ingólfsson, Helgi I; Thakur, Pratima; Herold, Karl F et al. (2014) Phytochemicals perturb membranes and promiscuously alter protein function. ACS Chem Biol 9:1788-98
Rusinova, Radda; Kim, Dorothy M; Nimigean, Crina M et al. (2014) Regulation of ion channel function by the host lipid bilayer examined by a stopped-flow spectrofluorometric assay. Biophys J 106:1070-8
Vorobyov, Igor; Olson, Timothy E; Kim, Jung H et al. (2014) Ion-induced defect permeation of lipid membranes. Biophys J 106:586-97
McCoy, Jason G; Rusinova, Radda; Kim, Dorothy M et al. (2014) A KcsA/MloK1 chimeric ion channel has lipid-dependent ligand-binding energetics. J Biol Chem 289:9535-46
Rusinova, Radda; Hobart, E Ashley; Koeppe 2nd, Roger E et al. (2013) Phosphoinositides alter lipid bilayer properties. J Gen Physiol 141:673-90
Bruno, Michael J; Rusinova, Radda; Gleason, Nicholas J et al. (2013) Interactions of drugs and amphiphiles with membranes: modulation of lipid bilayer elastic properties by changes in acyl chain unsaturation and protonation. Faraday Discuss 161:461-80; discussion 563-89
Lee, Kyu Ii; Pastor, Richard W; Andersen, Olaf S et al. (2013) Assessing smectic liquid-crystal continuum models for elastic bilayer deformations. Chem Phys Lipids 169:19-26
Tibbs, Gareth R; Rowley, Thomas J; Sanford, R Lea et al. (2013) HCN1 channels as targets for anesthetic and nonanesthetic propofol analogs in the amelioration of mechanical and thermal hyperalgesia in a mouse model of neuropathic pain. J Pharmacol Exp Ther 345:363-73
Kim, Taehoon; Lee, Kyu Il; Morris, Phillip et al. (2012) Influence of hydrophobic mismatch on structures and dynamics of gramicidin a and lipid bilayers. Biophys J 102:1551-60
Gu, Hong; Lum, Kevin; Kim, Jung H et al. (2011) The membrane interface dictates different anchor roles for "inner pair" and "outer pair" tryptophan indole rings in gramicidin A channels. Biochemistry 50:4855-66

Showing the most recent 10 out of 88 publications