Coarse-Grained Modeling of Membrane Protein Integration via the Sec Translocon

Integration into the cell membrane is a key step in the biogenesis of membrane proteins. Membrane protein integration takes place at the Sec translocon and typically occurs during the ribosomal translation of the protein sequence. The study of Sec-facilitated membrane protein integration is difficult due to the roles of long-timescale dynamics and ribosomal translation. We present a coarse-grained (CG) simulation approach that is capable of reaching the experimentally relevant (i.e., minute) timescales, while retaining the level of detail required to capture amino-acid sequence level properties. The CG model enables direct simulation of co-translational integration at the Sec translocon and analysis of the resulting trajectories provides mechanistic explanations for observed experimental data. We demonstrate the use of the developed CG model to investigate the experimentally observed forces exerted on a nascent protein during co-translational membrane integration. It has been observed experimentally that the force exerted on the nascent protein depends on various factors, including the number of amino-acids that have been translated, nascent protein charge, and nascent protein hydrophobicity. Importantly, the CG model captures the effect of these factors on the force exerted on the nascent protein, enabling further analysis of the calculated trajectories to determine how the observed forces relate to the underlying physical process