Statistical Mechanics of Integral Membrane Protein Assembly

TL;DR

This paper models the thermodynamics of membrane protein assembly, revealing how sequence-specific factors and mutations influence the stability and number of transmembrane segments through a statistical mechanics approach.

Contribution

It introduces a many-body statistical mechanics model to analyze membrane protein segment partitioning and the effects of mutations on stability and fluctuations.

Findings

Wildtype sequences have stable transmembrane segment numbers due to an energy gap.

Random mutations can destabilize the native structure, increasing fluctuations.

Assembly scenarios can produce the native structure without jamming phenomena.

Abstract

During the synthesis of integral membrane proteins (IMPs), the hydrophobic amino acids of the polypeptide sequence are partitioned mostly into the membrane interior and hydrophilic amino acids mostly into the aqueous exterior. We analyze the minimum free energy state of polypeptide sequences partitioned into alpha-helical transmembrane (TM) segments and the role of thermal fluctuations using a many-body statistical mechanics model. Results suggest that IMP TM segment partitioning shares important features with general theories of protein folding. For random polypeptide sequences, the minimum free energy state at room temperature is characterized by fluctuations in the number of TM segments with very long relaxation times. Simple assembly scenarios do not produce a unique number of TM segments and jamming phenomena interfere with segment placement. For sequences corresponding to IMPs, the minimum free energy structure with the wildtype number of segments is free of number fluctuations due to an anomalous gap in the energy spectrum, and simple assembly scenarios produce this structure. There is a threshold number of random point mutations beyond which the size of this gap is reduced so that the wildtype groundstate is destabilized and number fluctuations reappear.