Abstract
We have studied the mobility of the multidomain folding catalyst, protein disulfide isomerase (PDI), by a coarse-graining approach based on flexibility. We analyze our simulations of yeast PDI (yPDI) using measures of backbone movement, relative positions and orientations of domains, and distances between functional sites. We find that there is interdomain flexibility at every interdomain junction but these show very different characteristics. The extent of interdomain flexibility is such that yPDI's two active sites can approach much more closely than is found in crystal structures—and indeed hinge motion to bring these sites into proximity is the lowest energy normal mode of motion of the protein. The flexibility predicted for yPDI (based on one structure) includes the other known conformation of yPDI and is consistent with (i) the mobility observed experimentally for mammalian PDI and (ii) molecular dynamics. We also observe intradomain flexibility and clear differences between the domains in their propensity for internal motion. Our results suggest that PDI flexibility enables it to interact with many different partner molecules of widely different sizes and shapes, and highlights considerable similarities of yPDI and mammalian PDI. Proteins 2016; 84:1776–1785.
| Original language | English |
|---|---|
| Pages (from-to) | 1776-1785 |
| Number of pages | 10 |
| Journal | Proteins: Structure, Function and Bioinformatics |
| Volume | 84 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published - 1 Dec 2016 |
Funding
We thank Jack Heal, Mark Howard, Richard Williamson, and Mike Thorpe for inspiring discussions. S.A. Wells gratefully acknowledges the Leverhulme Trust for an Early Career Fellowship. We are grateful to the Royal Society and the Indian DST for support of a UKIERI Scientific Seminar and also the Warwick Institute of Advanced Study for funding the ?Protein Biology and BioPhysics? network as well as the EPSRC MOAC DTC for providing facilities. We are grateful to the EPSRC for provision of computing resources through the MidPlus Regional HPC Centre (EP/K000128/1). We thank the DBT, Govt. of India, for computational support for the MD simulations. S. Vishweshwara acknowledges CSIR emeritus scientist and NASI senior Scientist Fellowships. E.J.R., R.B.F., R.A.R., and S.A.W. planned the study. E.J.R. and S.A.W. ran the flexibility analysis; M.B. and S.V. computed the MD trajectories; E.J.R., M.B., and S.A.W. supplied the figure data while R.A.R., R.B.F., and S.A.W. selected and composed the graphs. All authors performed data analysis and discussed the results. R.A.R. and R.B.F. wrote the manuscript. All data are provided in full in the results section as well as the supplement of this article.
Keywords
- and computer simulation
- dynamics of biomolecules
- large-domain motion
- modeling
- PDI
- protein dynamics
- protein flexibility
- theory
ASJC Scopus subject areas
- Structural Biology
- Biochemistry
- Molecular Biology