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Published March 2017 | Published + Supplemental Material
Journal Article Open

Structurally detailed coarse-grained model for Sec-facilitated co-translational protein translocation and membrane integration

Abstract

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.

Additional Information

© 2017 Niesen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Received: November 1, 2016; Accepted: February 28, 2017; Published: March 22, 2017. Data Availability Statement: Data underlying the findings described in the manuscript are provided in the manuscript and in the supporting information. This work is supported by the Office of Naval Research (http://www.onr.navy.mil) under grant number N00014-10-1-0884 to TFM, and the National Institute of General Medical Sciences of the National Institutes of Health (https://www.nigms.nih.gov) under a Ruth L Kirschstein National Research Service Award award number 1F32GM113334-01 to RCVL. Additionally, TFM acknowledges support from a Camille Dreyfus Teacher-Scholar Award (http://www.dreyfus.org/awards/camille_dreyfus_teacher_award.shtml). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Computational resources were provided by the National Energy Research Scientific Computing Center (NERSC) and a DOE Office of Science User Facility (DE-AC02-05CH11231). Additionally, this work used computational resources through the Extreme Science and Engineering Discovery Environment (XSEDE) [79], which is supported by National Science Foundation grant number ACI-1053575. Author Contributions: Conceptualization: MJMN CYW RCVL TFM. Data curation: MJMN CYW RCVL TFM. Formal analysis: MJMN CYW RCVL TFM. Funding acquisition: RCVL TFM. Investigation: MJMN CYW RCVL TFM. Methodology: MJMN CYW RCVL TFM. Project administration: TFM. Resources: TFM. Software: MJMN CYW RCVL TFM. Supervision: TFM. Validation: MJMN CYW RCVL TFM. Visualization: MJMN CYW RCVL TFM. Writing ± original draft: MJMN CYW RCVL TFM. Writing ± review & editing: MJMN CYW RCVL TFM. The authors have declared that no competing interests exist.

Attached Files

Published - journal.pcbi.1005427.pdf

Supplemental Material - journal.pcbi.1005427.s001.pdf

Supplemental Material - journal.pcbi.1005427.s002.pdf

Supplemental Material - journal.pcbi.1005427.s003.pdf

Supplemental Material - journal.pcbi.1005427.s004.mp4

Supplemental Material - journal.pcbi.1005427.s005.mp4

Supplemental Material - journal.pcbi.1005427.s006.mp4

Supplemental Material - journal.pcbi.1005427.s007.mp4

Supplemental Material - journal.pcbi.1005427.s008.xlsx

Supplemental Material - journal.pcbi.1005427.s009.xlsx

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August 19, 2023
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