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

Abstract

This paper reports a method for high-accuracy protein structural refinement, which is a direct extension of the method in our recent publication (Zang, J Chem Phys 2018; 149:072319). It combines a parallel continuous simulated tempering (PCST) method with a temperature-dependent restraint and a blind model selection scheme. In this work, a single-reference-based restraint in previous work was changed to an ensemble-based model (EBM), in which the non-bonded Lennard-Jones term for each contacting atomic pair in previous restraining potential was replaced by a multi-Gaussian function whose parameters are derived from an ensemble of structures such as the ones from various CASP participating groups. The purpose of EBM is to take advantage of partial "correctness" distributed among members of the structural ensemble. Totally 18 targets were refined from the refinement category of CASP10, CASP11 and CASP12. In Top-1 group, 11 out of 18 targets had better models (greater GDT_TS scores) than the CASPR participants. In Top-5 group, nine out of 18 were better. Our results show that PCST-EBM method can considerably improve the low-accuracy structures.

CryoEM reveals oligomeric isomers of a multienzyme complex and assembly mechanics

“…If the cells are thin enough, not only can we determine structural conformations in solution but also those in situ ( Xue et al, 2022 , Chmielewski et al, 2022 , Liu et al, 2020 ). Such prospects offer exciting opportunities for experimentally “visualizing” statistical mechanics within an enormous conformational space, and to assist drug design in targeting the rate-limiting step of a complex of interest’s assembly ( Giraldo-Barreto et al, 2021 , Chen and Ludtke, 2021 , Zhou et al, 2022 , Ma et al, 2018 ). Taking advantage of the limited number of conformational isomers of PCC, the current work showcases the utility of cryoEM beyond determining static structures towards statistical analysis of thermodynamics and structural dynamics.…”

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.…”

CryoEM Reveals Oligomeric Isomers of a Multienzyme Complex and Assembly Mechanics

“…In fact, if the cells are thin enough, we not only can determine structural conformations in solution but also in situ [29,33,34]. Such prospects offer exciting opportunities for experimentally "visualizing" statistical mechanics within an enormous conformational space, and to assist drug design in targeting the rate-limiting step of a complex of interest's assembly [35][36][37][38]. Taking advantage of the limited number of conformational isomers of PCC, the current work showcases the utility of cryoEM beyond determining static structures towards statistical analysis of thermodynamics and structural dynamics.…”