Prediction of protein structure with the coarse‐grained UNRES force field assisted by small X‐ray scattering data and knowledge‐based information

Abstract

A new approach to assisted protein-structure prediction has been proposed, which is based on running multiplexed replica exchange molecular dynamics simulations with the coarse-grained UNRES force field with restraints derived from knowledge-based models and distance distribution from small angle X-ray scattering (SAXS) measurements. The latter restraints are incorporated into the target function as a maximum-likelihood term that guides the shape of the simulated structures towards that defined by SAXS. The approach was first verified with the 1KOY protein, for which the distance distribution was calculated from the experimental structure, and subsequently used to predict the structures of 11 data-assisted targets in the CASP12 experiment. Major improvement of the GDT_TS was obtained for 2 targets, minor improvement for other 2 while, for 6 target GDT_TS deteriorated compared with that calculated for predictions without the SAXS data, partly because of assuming a wrong multimeric state (for Ts866) or because the crystal conformation was more compact than the solution conformation (for Ts942). Particularly good results were obtained for Ts909, in which use of SAXS data resulted in the selection of a correctly packed trimer and, subsequently, increased the GDT_TS of monomer prediction. It was found that running simulations with correct oligomeric state is essential for the success in SAXS-data-assisted prediction.

Insights into the structure and dynamics of lysyl oxidase propeptide, a flexible protein with numerous partners

“…It should be noted that the above models did not take into account the glycosylation of LOX-PP, whereas SAXS experiments were carried out with glycosylated LOX-PP. We generated theoretical 1D SAXS profile for each model using the Cα-Cα distances and the Gaussian smoothing as described in our recent work 31 . The models that best fitted the experimental 1D SAXS profile were models 1 and 2 with normalized χ 2 values being 0.48 and 0.51 respectively.…”

“…3D models of LOX-PP were generated using the UNRES coarse-grained model of proteins 70 , 71 with the recently added function of including the distance distribution from SAXS as restraints 31 . The full protocol is detailed in Supplementary material.…”

UNRES server for physics-based coarse-grained simulations and prediction of protein structure, dynamics and thermodynamics

“…In the basic input mode, an REMD calculation (no multiplexing) is carried out with eight replicas run at temperatures from 270 K to 345 K. In the advanced mode, the user can choose the number of replica temperatures and the values of the temperatures, as well as multiplexing of each replica and replica-exchange frequency. In addition to this, the distance distribution from small x-ray scattering (SAXS) measurements can be input to run SAXS-restrained simulations ( 32 ). MD parameters can be selected in the advanced mode, as for MD-type runs.…”

Recent Advances in Coarse-Grained Models for Biomolecules and Their Applications

“…The force field is based upon solid statistical mechanics and various MD-related methods have been used for sampling [39]. It had been extensively used for protein folding studies, protein structure prediction, protein-DNA interaction, signaling mechanism, action of chaperones and amyloid formation [81][82][83][84][85]. In an effort from Sieradzan et al, steered molecular dynamics was implemented to the UNRES force field [44].…”