RT Journal Article
SR Electronic
T1 Origin of Conformational Dynamics in a Globular Protein
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 724286
DO 10.1101/724286
A1 Adam M. Damry
A1 Marc M. Mayer
A1 Aron Broom
A1 Natalie K. Goto
A1 Roberto A. Chica
YR 2019
UL http://biorxiv.org/content/early/2019/08/04/724286.abstract
AB Protein structures are dynamic, undergoing specific motions that can play a vital role in function. However, the link between primary sequence and conformational dynamics remains poorly understood. Here, we studied how conformational dynamics can arise in a globular protein by evaluating the impact of individual substitutions of core residues in DANCER-3, a streptococcal protein G domain β1 (Gβ1) variant that we previously designed to undergo a specific mode of conformational exchange that has never been observed in the wild-type protein. Using a combination of solution NMR experiments and molecular dynamics simulations, we demonstrate that only two mutations are necessary to create this conformational exchange, and that these mutations work synergistically, with one destabilizing the native Gβ1 structure and the other allowing two new conformational states to be accessed on the energy landscape. Overall, our results show how conformational dynamics can appear in a stable globular fold, a critical step in the molecular evolution of new dynamics-linked functions.