Knowledge of Native Protein鈥揚rotein Interfaces Is Sufficient To Construct Predictive Models for the Selection of Binding Candidates
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- 作者：Petr Popov ; Sergei Grudinin
- 刊名：Journal of Chemical Information and Modeling
- 出版年：2015
- 出版时间：October 26, 2015
- 年：2015
- 卷：55
- 期：10
- 页码：2242-2255
- 全文大小：669K
- ISSN：1549-960X
文摘
Selection of putative binding poses is a challenging part of virtual screening for protein鈥損rotein interactions. Predictive models to filter out binding candidates with the highest binding affinities comprise scoring functions that assign a score to each binding pose. Existing scoring functions are typically deduced by collecting statistical information about interfaces of native conformations of protein complexes along with interfaces of a large generated set of non-native conformations. However, the obtained scoring functions become biased toward the method used to generate the non-native conformations, i.e., they may not recognize near-native interfaces generated with a different method. The present study demonstrates that knowledge of only native protein鈥損rotein interfaces is sufficient to construct well-discriminative predictive models for the selection of binding candidates. Here we introduce a new scoring method that comprises a knowledge-based potential called KSENIA deduced from structural information about the native interfaces of 844 crystallographic protein鈥損rotein complexes. We derive KSENIA using convex optimization with a training set composed of native protein complexes and their near-native conformations obtained using deformations along the low-frequency normal modes. As a result, our knowledge-based potential has only marginal bias toward a method used to generate putative binding poses. Furthermore, KSENIA is smooth by construction, which allows it to be used along with rigid-body optimization to refine the binding poses. Using several test benchmarks, we demonstrate that our method discriminates well native and near-native conformations of protein complexes from non-native ones. Our methodology can be easily adapted to the recognition of other types of molecular interactions, such as protein鈥搇igand, protein鈥揜NA, etc. KSENIA will be made publicly available as a part of the SAMSON software platform at https://team.inria.fr/nano-d/software.