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.
Highlights
Most integral membrane proteins (IMPs) are co-translationally inserted into the membrane during biosynthesis via the Sec translocon, a multiprotein complex [1,2,3,4]
transmembrane domains (TMDs) typically contain a large number of hydrophobic residues to improve stability within the lipid membrane [74]. von Heijne and co-workers measured the probability with which a designed segment (H-segment) of the leader peptidase (Lep) protein integrates into the membrane, demonstrating that the translocon is more likely to integrate hydrophobic nascent polypeptide chain (NC) segments [51]
It was found that increasing the hydrophobicity of a poly-alanine H-segment, through mutation of alanine residues to leucine residues, monotonically increased the probability of Hsegment membrane integration
Summary
Most integral membrane proteins (IMPs) are co-translationally inserted into the membrane during biosynthesis via the Sec translocon, a multiprotein complex [1,2,3,4]. In this process, a ribosome docks to the cytosolic opening of the Sec translocon and feeds a nascent polypeptide chain (NC) into the translocon channel. The likelihood of integration or translocation of polypeptide segments depends on residue-specific chemical features of the nascent polypeptide chain, such as its hydrophobicity and charge [8,9,10,11,12], but is governed by the dynamics of protein synthesis on the minute timescale [13, 14]
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