Improving low-accuracy protein structures using enhanced sampling techniques

Abstract

In this paper, we report results of using enhanced sampling and blind selection techniques for high-accuracy protein structural refinement. By combining a parallel continuous simulated tempering (PCST) method, previously developed by Zang [J. Chem. Phys., 044113 (2014)], and the structure based model (SBM) as restraints, we refined 23 targets (18 from the refinement category of the CASP10 and 5 from that of CASP12). We also designed a novel model selection method to blindly select high-quality models from very long simulation trajectories. The combined use of PCST-SBM with the blind selection method yielded final models that are better than initial models. For Top-1 group, 7 out of 23 targets had better models (greater global distance test total scores) than the critical assessment of structure prediction participants. For Top-5 group, 10 out of 23 were better. Our results justify the crucial position of enhanced sampling in protein structure prediction and refinement and demonstrate that a considerable improvement of low-accuracy structures is achievable with current force fields.

Forging tools for refining predicted protein structures

“…In actual blacksmithing, repeated heating and cooling of the sample is an important aspect. A natural extension of the current protocol would be to combine PC-guided mechanical deformations with continuous simulated tempering, which performs a guided random walk in temperature space (45,46). One might also consider performing Hamiltonian replica exchange simulations with replicas that have different strengths of the side-chain rotamer isomerization barriers to harness the speedup allowed by lowering the barriers without sacrificing the structural specificity attained when using the full barrier heights.…”

Refining protein structures using enhanced sampling techniques with restraints derived from an ensemble‐based model

“…4–8 Å) and there are no other atoms between them, we consider this atom pairs are considered as contacts. The details can be found in our previous PCST‐SBM paper …”

“…In our previous paper, in order to improve the low‐accuracy protein structural models, the parallel continuous simulated tempering (PCST) was combined with a temperature‐dependent restraint using structure‐based model (SBM) . In fully solvated molecular dynamics simulation for refinement, it was shown that PCST‐SBM method was able to achieve a more thorough sampling in the configurational space.…”

“…A distinct weakness of SBM restraint, which is derived from a single reference structure, is that the reference structure may itself carry large errors either partially or entirely. These errors can hinder the refinement accuracy.…”

“…In EBM restraint, the non‐bonded Lennard–Jones term for each contacting atomic pair in SBM restraint is replaced by a multi‐Gaussian function. The parameters for the multi‐Gaussian function are determined by fitting the radial distribution function of the contact distance in an ensemble of structures.…”