Membrane Protein Function And Transmembrane Helix Backbone Dynamics

The backbones of transmembrane helices are dynamic in a sense that they unfold locally and transiently on nanosecond timescales. We would like to review our results on the backbone dynamics of diverse natural and de novo designed transmembrane helix peptides by deuterium/hydrogen-exchange experiments and Molecular Dynamics simulations. Our findings suggest that amino acids that are known to be helix-destabilizing enhance dynamics. Thus, helix dynamics is sequence-dependent and protein functions depending on it can be optimized during evolution. In one example, we studied the implications of TM helix dynamics for the mechanism of membrane fusion. We will present data indicating that enhanced TM-helix dynamics supports lipid mixing. In the second case, we show that TM helix dynamics correlates with the ability of TM peptides to induce lipid flip. In a third example, we investigated the backbone dynamics of the transmembrane domain of the amyloid precursor protein implicated in Alzheimers disease. This is motivated by the idea that proteolytic processing by gamma-secretase requires local backbone unfolding. The results show how the dynamics of the APP TM-helix is distributed over the different proteolytic cleavage sites and how it depends on critical amino acids.