Solving protein structures using short-distance cross-linking constraints as a guide for discrete molecular dynamics simulations.

Sci Adv. 2017 Jul 7;3(7):e1700479. doi: 10.1126/sciadv.1700479. eCollection 2017 Jul.
Brodie NI, Popov KI, Petrotchenko EV, Dokholyan NV, Borchers CH

We present an integrated experimental and computational approach for de novo protein structure determination in which short-distance cross-linking data are incorporated into rapid discrete molecular dynamics (DMD) simulations as constraints, reducing the conformational space and achieving the correct protein folding on practical time scales. We tested our approach on myoglobin and FK506 binding protein-models for α helix-rich and β sheet-rich proteins, respectively-and found that the lowest-energy structures obtained were in agreement with the crystal structure, hydrogen-deuterium exchange, surface modification, and long-distance cross-linking validation data. Our approach is readily applicable to other proteins with unknown structures.