Structurally detailed coarse-grained model for Sec-facilitated co-translational protein translocation and membrane integration.
We present a coarse-grained simulation model that is capable of simulating the minute-timescale dynamics of protein translocation and membrane integration via the Sec translocon, while retaining sufficient chemical and structural detail to capture many of the sequence-specific interactions that drive these processes. The model includes accurate geometric representations of the ribosome and Sec translocon, obtained directly from experimental structures, and interactions parameterized from nearly 200 μs of residue-based coarse-grained molecular dynamics simulations. A protocol for mapping amino-acid sequences to coarse-grained beads enables the direct simulation of trajectories for the co-translational insertion of arbitrary polypeptide sequences into the Sec translocon. The model reproduces experimentally observed features of membrane protein integration, including the efficiency with which polypeptide domains integrate into the membrane, the variation in integration efficiency upon single amino-acid mutations, and the orientation of transmembrane domains. The central advantage of the model is that it connects sequence-level protein features to biological observables and timescales, enabling direct simulation for the mechanistic analysis of co-translational integration and for the engineering of membrane proteins with enhanced membrane integration efficiency.
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California, United States of America.
Michiel J M
0000-0002-9255-6203
MJ
Niesen
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California, United States of America.
Connie Y
0000-0003-2971-3971
CY
Wang
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California, United States of America.
Reid C
0000-0003-4885-6599
RC
Van Lehn
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California, United States of America.
Thomas F
TF
Miller
D001665:Binding Sites; D002462:Cell Membrane / Q000737:chemistry / Q000648:ultrastructure; D008051:Lipid Bilayers / Q000737:chemistry*; D008956:Models, Chemical; D056004:Molecular Dynamics Simulation; D009038:Motion; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D000069284:Protein Translocation Systems / Q000737:chemistry* / Q000648:ultrastructure*; D021381:Protein Transport; D012270:Ribosomes / Q000737:chemistry / Q000648:ultrastructure; D000069816:SEC Translocation Channels / Q000737:chemistry* / Q000648:ultrastructure*
D008051:Lipid Bilayers; D000069284:Protein Translocation Systems; D000069816:SEC Translocation Channels