NERSC Initiative for Scientific Exploration (NISE) 2009 Awards

Studies of the Sec translocase Transmembrane Channel in Protein Synthesis

Thomas Miller, California Institute of Technology

Sponsoring NERSC Project: Sampling Diffusive Dynamics on Long Timescales, and Simulating the Coupled Dynamics of Electrons and Nuclei (m822), Principal Investigator: Thomas Miller, California Institute of Technology

A critical step in the biosynthesis of many proteins involves either translocating a cellular membrane or integrating into a cellular membrane. Both processes proceed via the Sec translocase - a ubiquitous and highly conserved transmembrane channel. Recent structural studies offer high-resolution glimpses into the translocation process, and genetic studies reveal that the Sec channel is a potential target for cancer therapeutics, but many fundamental aspects of its mechanism and regulation remain unclear. Using novel coarse-graining techniques, my research group has recently discovered that hydrophobic proteins inserted into the Sec channel can stabilize a previously unobserved open state for the channel, which is thought to play a key role in regulating the translocation vs. integration pathways. We are currently extending long-timescale trajectory sampling methods and rare-event sampling techniques to address (i) the mechanism by which targeted proteins are delivered to and positioned for the channel, (ii) the role of specific amino-acid residues and steric interactions in the regulation of targeted proteins and the preservation of the transmembrane ion gradient, and (iii) the importance of membrane fluctuations and channel flexibility in the dynamics and regulation of translocation. This work will yield a unified picture for this fundamental biological pathway, as well as new pharmaceutical strategies for cancer inhibition and treatment.