The flexibility and dynamics of protein disulfide isomerase.
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. © 2016 Wiley Periodicals, Inc.
Department of Physics and Centre for Scientific Computing, The University of Warwick, Coventry, CV4 7AL, United Kingdom.
Rudolf A
RA
Römer
Department of Chemical Engineering, University of Bath, Bath, BA2 7AY, United Kingdom.
Stephen A
SA
Wells
Department of Physics and Centre for Scientific Computing, The University of Warwick, Coventry, CV4 7AL, United Kingdom.
J
J
Emilio Jimenez-Roldan
Molecular Biophysics Unit, Indian Institute of Science, Bangalore, 560012, India.
Moitrayee
M
Bhattacharyya
Molecular Biophysics Unit, Indian Institute of Science, Bangalore, 560012, India.
Saraswathi
S
Vishweshwara
School of Life Sciences, The University of Warwick, Coventry, CV4 7AL, United Kingdom.
Robert B
RB
Freedman
D001665:Binding Sites; D015870:Gene Expression; D056004:Molecular Dynamics Simulation; D018583:Pliability; D011485:Protein Binding; D019704:Protein Disulfide-Isomerases / Q000737:chemistry*; D017510:Protein Folding; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D012441:Saccharomyces cerevisiae / Q000737:chemistry* / Q000201:enzymology; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013816:Thermodynamics
C080576:PDI1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D019704:Protein Disulfide-Isomerases
PDI; and computer simulation; dynamics of biomolecules; large-domain motion; modeling; protein dynamics; protein flexibility; theory