The dynamics and flexibility of protein disulphide-isomerase (PDI): predictions of experimentally-observed domain motions

TL;DR

This study combines molecular dynamics and a rapid flexibility approach to analyze the domain motions of protein disulphide-isomerase, revealing dominant hinge and rotation movements and identifying the highly mobile a' domain.

Contribution

It demonstrates that a computationally efficient flexibility method can predict large-scale inter-domain motions consistent with experimental observations, complementing molecular dynamics simulations.

Findings

Domain motion dominated by hinge and rotation of a and a' domains

a' domain exhibits the greatest intra-domain mobility

Flexibility method predicts large-scale inter-domain motions consistent with experiments

Abstract

We have studied the mobility of the folding catalyst, protein disulphide-isomerase (PDI), by molecular dynamics and by a rapid approach based on flexibility. We analysed our simulations using measures of backbone movement, relative positions and orientations of domains, and distances between functional sites. Despite their different assumptions, the two methods are surprisingly consistent. Both methods agree that motion of domains is dominated by hinge and rotation motion of the a and a' domains relative to the central b-b' domain core. We identify the a' domain as showing the greatest intra-domain mobility. The flexibility method, which requires 10^4-fold less computer power, predicts additional large-scale features of inter-domain motion that have been observed experimentally. We conclude that the methods offer complementary insight into the motion of this large protein and provide detailed structural models that characterise its functionally-significant conformational changes.