TY - JOUR
T1 - A population-based evolutionary search approach to the multiple minima problem in de novo protein structure prediction
AU - Saleh, Sameh
AU - Olson, Brian
AU - Shehu, Amarda
N1 - Funding Information:
This work is supported in part by NSF CCF No. 1016995 and NSF IIS CAREER Award No. 1144106. We thank members of the Shehu lab for their valuable comments on this work and the Mason OSCAR program supporting undergraduate research for a fellowship to SS during the initial phases of this project.
Funding Information:
The publication costs for this article were funded by the corresponding author AS through NSF Grant Nos. 1016995 and 1144106. This article has been published as part of BMC Structural Biology Volume 13 Supplement 1, 2013: Selected articles from the Computational Structural Bioinformatics Workshop 2012. The full contents of the supplement are available online at http://www.biomedcentral.com/bmcstructbiol/ supplements/13/S1.
PY - 2013
Y1 - 2013
N2 - Background: Elucidating the native structure of a protein molecule from its sequence of amino acids, a problem known as de novo structure prediction, is a long standing challenge in computational structural biology. Difficulties in silico arise due to the high dimensionality of the protein conformational space and the ruggedness of the associated energy surface. The issue of multiple minima is a particularly troublesome hallmark of energy surfaces probed with current energy functions. In contrast to the true energy surface, these surfaces are weakly-funneled and rich in comparably deep minima populated by non-native structures. For this reason, many algorithms seek to be inclusive and obtain a broad view of the low-energy regions through an ensemble of low-energy (decoy) conformations. Conformational diversity in this ensemble is key to increasing the likelihood that the native structure has been captured. Methods. We propose an evolutionary search approach to address the multiple-minima problem in decoy sampling for de novo structure prediction. Two population-based evolutionary search algorithms are presented that follow the basic approach of treating conformations as individuals in an evolving population. Coarse graining and molecular fragment replacement are used to efficiently obtain protein-like child conformations from parents. Potential energy is used both to bias parent selection and determine which subset of parents and children will be retained in the evolving population. The effect on the decoy ensemble of sampling minima directly is measured by additionally mapping a conformation to its nearest local minimum before considering it for retainment. The resulting memetic algorithm thus evolves not just a population of conformations but a population of local minima. Results and conclusions. Results show that both algorithms are effective in terms of sampling conformations in proximity of the known native structure. The additional minimization is shown to be key to enhancing sampling capability and obtaining a diverse ensemble of decoy conformations, circumventing premature convergence to sub-optimal regions in the conformational space, and approaching the native structure with proximity that is comparable to state-of-the-art decoy sampling methods. The results are shown to be robust and valid when using two representative state-of-the-art coarse-grained energy functions.
AB - Background: Elucidating the native structure of a protein molecule from its sequence of amino acids, a problem known as de novo structure prediction, is a long standing challenge in computational structural biology. Difficulties in silico arise due to the high dimensionality of the protein conformational space and the ruggedness of the associated energy surface. The issue of multiple minima is a particularly troublesome hallmark of energy surfaces probed with current energy functions. In contrast to the true energy surface, these surfaces are weakly-funneled and rich in comparably deep minima populated by non-native structures. For this reason, many algorithms seek to be inclusive and obtain a broad view of the low-energy regions through an ensemble of low-energy (decoy) conformations. Conformational diversity in this ensemble is key to increasing the likelihood that the native structure has been captured. Methods. We propose an evolutionary search approach to address the multiple-minima problem in decoy sampling for de novo structure prediction. Two population-based evolutionary search algorithms are presented that follow the basic approach of treating conformations as individuals in an evolving population. Coarse graining and molecular fragment replacement are used to efficiently obtain protein-like child conformations from parents. Potential energy is used both to bias parent selection and determine which subset of parents and children will be retained in the evolving population. The effect on the decoy ensemble of sampling minima directly is measured by additionally mapping a conformation to its nearest local minimum before considering it for retainment. The resulting memetic algorithm thus evolves not just a population of conformations but a population of local minima. Results and conclusions. Results show that both algorithms are effective in terms of sampling conformations in proximity of the known native structure. The additional minimization is shown to be key to enhancing sampling capability and obtaining a diverse ensemble of decoy conformations, circumventing premature convergence to sub-optimal regions in the conformational space, and approaching the native structure with proximity that is comparable to state-of-the-art decoy sampling methods. The results are shown to be robust and valid when using two representative state-of-the-art coarse-grained energy functions.
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U2 - 10.1186/1472-6807-13-S1-S4
DO - 10.1186/1472-6807-13-S1-S4
M3 - Article
C2 - 24565020
AN - SCOPUS:84887468789
SN - 1472-6807
VL - 13
JO - BMC Structural Biology
JF - BMC Structural Biology
IS - SUPPL.1
M1 - S4
ER -