by
Prof.Erik Lindahl(KTH Theoretical & Computational Biophysics)
→
Europe/Stockholm
122:026
122:026
Description
Membrane proteins constitute one of the most fascinating classes of biological macromolecules. In a typical genome, roughly 30% of the genes code for proteins associated with membranes, but since these proteins are present on the cell surface they are of extremely high importance efor pharmaceutical applications. Over half of currently available drugs target membrane proteins, and in terms of market value it is close to 80%. Due to difficulties in overexpression and crystallization there are still only a couple of hundred membrane protein structures known, and for this reason sequence-based modeling of membrane proteins has received a lot of attention. While most transmembrane segments in proteins are clearly hydrophobic, there are surprisingly enough a number of exceptions where marginally stable or even hydrophilic segments appear in the hydrophobic region. Many of these are critically important, for instance the S4 segments of voltage-gated ion channels - it is the charged residues inside these protein that causes the channel to open and close in response to voltages, which we need for every nerve impulse and heart beat. There has been significant debate between experimental results that claim insertion for these is quite cheap, and theoretical calculations claiming it is prohibitively expensive.
We use a fairly wide combination methods to study these systems, ranging from bioinformatics through modeling and large-scale distributed molecular simulations to statistical analysis of experiments. I will discuss these methods and talk about recent work where we have shown that the hydrophobicity values derived from experimental insertion is amazingly efficient at predicting insertion, how this can be used to understand (and predict) helix-helix interactions in membranes, and how we now likely can explain the molecular step of the insertion. I will also discuss how this related to some of our very recent results on structural changes in ion channel gating, where the charged S4 residues play a crucial role.
