Efficient Sampling of Protein Loop Regions Using Conformational Hashing Complemented with Random Coordinate Descent
| Autor: | Nathan Alexander, Axel Fischer, Jeffrey L. Mendenhall, Nicholas J Hyman, Jens Meiler, Diego del Alamo, Rocco Moretti |
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| Rok vydání: | 2020 |
| Předmět: |
Models
Molecular Loop (graph theory) Protein Conformation Computer science Random coordinate descent Hash function Proteins Sampling (statistics) Computer Science Applications Set (abstract data type) Range (mathematics) Benchmark (computing) Thermodynamics Computer Simulation Physical and Theoretical Chemistry Databases Protein Coordinate descent Algorithm Algorithms |
| Zdroj: | Journal of Chemical Theory and Computation. 17:560-570 |
| ISSN: | 1549-9626 1549-9618 |
| Popis: | De novo construction of loop regions is an important problem in computational structural biology. Compared to regions with well-defined secondary structure, loops tend to exhibit significant conformational heterogeneity. As a result, their structures are often ambiguous when determined using experimental data obtained by crystallography, cryo-EM, or NMR. Although structurally diverse models could provide a more relevant representation of proteins in their native states, obtaining large numbers of biophysically realistic and physiologically relevant loop conformations is a resource-consuming task. To address this need, we developed a novel loop construction algorithm, Hash/RCD, that combines knowledge-based conformational hashing with random coordinate descent (RCD). This hybrid approach achieved a closure rate of 100% on a benchmark set of 195 loops in 29 proteins that range from 3 to 31 residues. More importantly, the use of templates allows Hash/RCD to maintain the accuracy of state-of-the-art coordinate descent methods while reducing sampling time from over 400 to 141 ms. These results highlight how the integration of coordinate descent with knowledge-based sampling overcomes barriers inherent to either approach in isolation. This method may facilitate the identification of native-like loop conformations using experimental data or full-atom scoring functions by allowing rapid sampling of large numbers of loops. In this manuscript, we investigate and discuss the advantages, bottlenecks, and limitations of combining conformational hashing with RCD. By providing a detailed technical description of the Hash/RCD algorithm, we hope to facilitate its implementation by other researchers. |
| Databáze: | OpenAIRE |
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