Computational Approach to Study Membrane Protein Topology

Abstract

Membrane proteins represent an important class of proteins with a variety of biological functions and a major fundamental and pharmaceutical interest. The protein-conducting channel translocon is responsible for protein-membrane integration. Despite significant progress it is unknown how membrane proteins achieve different topologies. Experimental studies suggest that the location of the positive charges on the signal peptide may influence its orientation (so-called “positive-inside” rule). In addition the topology of the membrane proteins may be affected by the prl (protein localization) mutations on the translocon. In this study we tried to estimate the barrier for the polypeptide insertion into the translocon using our renormalization approach (1). In this approach the insertion dynamics is first simulated with coarse grain model (2) where the whole insertion profile is divided on intermediate states and the time dependence response of each step is obtained. The second step involves the simulation with an implicit Langevin Dynamics (LD) model of reduced dimensions. By adjusting the friction and the barrier of the implicit LD model we can get the agreement between the time dependence responses of both models. By combining the barriers from different intermediate steps we can get the barrier for the whole insertion process. The renormalization approach allowed us to compare the barriers for different signal peptides, as well as to study the effect of mutations of the translocon on the orientation of the signal peptide. (1) Kamerlin et al., Annual Reviews, 2010. (2) Rychkova et al., PNAS, 2010.