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Direct Simulation of Early-Stage Sec-Facilitated Protein Translocation

Zhang, Bin and Miller, Thomas F., III (2012) Direct Simulation of Early-Stage Sec-Facilitated Protein Translocation. Journal of the American Chemical Society, 134 (33). pp. 13700-13707. ISSN 0002-7863. PMCID PMC3431202. doi:10.1021/ja3034526.

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Direct simulations reveal key mechanistic features of early-stage protein translocation and membrane integration via the Sec-translocon channel. We present a novel computational protocol that combines non-equilibrium growth of the nascent protein with microsecond timescale molecular dynamics trajectories. Analysis of multiple, long timescale simulations elucidates molecular features of protein insertion into the translocon, including signal-peptide docking at the translocon lateral gate (LG), large lengthscale conformational rearrangement of the translocon LG helices, and partial membrane integration of hydrophobic nascent-protein sequences. Furthermore, the simulations demonstrate the role of specific molecular interactions in the regulation of protein secretion, membrane integration, and integral membrane protein topology. Salt-bridge contacts between the nascent-protein N-terminus, cytosolic translocon residues, and phospholipid head groups are shown to favor conformations of the nascent protein upon early-stage insertion that are consistent with the Type II (N_(cyt)/C_(exo)) integral membrane protein topology, and extended hydrophobic contacts between the nascent protein and the membrane lipid bilayer are shown to stabilize configurations that are consistent with the Type III (N_(exo)/C_(cyt)) topology. These results provide a detailed, mechanistic basis for understanding experimentally observed correlations between integral membrane protein topology, translocon mutagenesis, and nascent-protein sequence.

Item Type:Article
Related URLs:
URLURL TypeDescription CentralArticle
Zhang, Bin0000-0002-3685-7503
Miller, Thomas F., III0000-0002-1882-5380
Additional Information:© 2012 American Chemical Society. Received: April 11, 2012. Published: August 1, 2012. This research was supported in part by the U.S. Office of Naval Research (USONR) under Grant No. N00014-10-1-0884 and the Department of Energy under Grant No. DE-SC0006598. Additionally, T.F.M. acknowledges an Alfred P. Sloan Foundation fellowship. We acknowledge use of the Anton supercomputer system that is hosted by the National Resource for Biomedical Supercomputing (NRBSC) at the Pittsburgh Supercomputing Center (PSC), with funding from the National Institute of General Medical Sciences under grant RC2GM093307, as well as computing resources from the National Science Foundation under Grant No. CHE-1040558. The authors declare no competing financial interest.
Funding AgencyGrant Number
Office of Naval Research (ONR)N00014-10-1-0884
Department of Energy (DOE)DE-SC0006598
Alfred P. Sloan FoundationUNSPECIFIED
Issue or Number:33
PubMed Central ID:PMC3431202
Record Number:CaltechAUTHORS:20121031-134552173
Persistent URL:
Official Citation:Direct Simulation of Early-Stage Sec-Facilitated Protein Translocation Bin Zhang and Thomas F. Miller, III Journal of the American Chemical Society 2012 134 (33), 13700-13707
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:35211
Deposited By: Tony Diaz
Deposited On:01 Nov 2012 18:04
Last Modified:09 Nov 2021 23:13

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