Improving membrane protein expression by optimizing simulated integration efficiency

Integral membrane proteins (IMPs) are critical for the transport of information and matter across the cell membrane. However, their study is often hindered by difficulties in obtaining sufficient purified IMP using heterologous overexpression.

Co-translational insertion into the cell membrane via the Sec translocon is a key step in the production of IMPs. However, both experimental and computational studies of this process are difficult due to the role of long-timescale non-equilibrium dynamics during ribosomal translation. We have developed a coarse-grained molecular dynamics (CGMD) approach that is capable of reaching experimentally relevant (i.e. minute) timescales, while retaining the level of detail required to capture the effect of individual amino-acid substitutions.

Using a combination of simulations of IMP integration and experimental quantification of IMP expression levels; we demonstrate a link between the efficiency of IMP integration into the cell membrane and IMP expression, yielding a powerful tool for the rational prediction of sequence modifications that improve expression.