Toward a detailed understanding of search trajectories in fragment assembly approaches to protein structure prediction

Proteins
Shaun M KandathilJulia Handl

Abstract

Energy functions, fragment libraries, and search methods constitute three key components of fragment-assembly methods for protein structure prediction, which are all crucial for their ability to generate high-accuracy predictions. All of these components are tightly coupled; efficient searching becomes more important as the quality of fragment libraries decreases. Given these relationships, there is currently a poor understanding of the strengths and weaknesses of the sampling approaches currently used in fragment-assembly techniques. Here, we determine how the performance of search techniques can be assessed in a meaningful manner, given the above problems. We describe a set of techniques that aim to reduce the impact of the energy function, and assess exploration in view of the search space defined by a given fragment library. We illustrate our approach using Rosetta and EdaFold, and show how certain features of these methods encourage or limit conformational exploration. We demonstrate that individual trajectories of Rosetta are susceptible to local minima in the energy landscape, and that this can be linked to non-uniform sampling across the protein chain. We show that EdaFold's novel approach can help balance broad explora...Continue Reading

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Citations

Feb 26, 2016·Evolutionary Computation·Mario Garza-FabreSimon C Lovell
Nov 15, 2017·Bioinformatics·Saulo H P de OliveiraCharlotte M Deane
Sep 14, 2018·Scientific Reports·Shaun M KandathilSimon C Lovell

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Methods Mentioned

BETA
MDS
protein folding

Software Mentioned

PSIPRED
EdaFold
MDS
BLAST
R
PAM
EdaFoldAA
Rosetta
PSI
AbinitioRelax

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