Binding Site Vectors Enable Mapping of Cytochrome P450 Functional Landscapes
Tea Kuvek, Zuzana Jandová, Klaus-Juergen Schleifer, Chris Oostenbrink
TL;DR
This paper introduces a new method to compare protein binding sites, revealing functional relationships in cytochrome P450 enzymes that traditional methods miss.
Contribution
The novel contribution is the development of binding site vectors that integrate structural and electrostatic features for high-resolution comparisons.
Findings
Binding site vectors reveal structural-functional relationships in CYP enzymes missed by sequence-based methods.
Analysis of over 600 CYP structures and MD ensembles shows the method's robustness in functional classification.
Including conformational ensembles enhances the detection of mechanistic insights in macromolecular systems.
Abstract
Understanding similarities between protein binding sites has long been of great interest, as such comparisons can reveal functional relationships that transcend sequence or fold. However, systematic comparison remains challenging due to the difficulty of defining active sites consistently and developing descriptors that are both general and discriminative. We present binding site vectors, a computational framework for a high-resolution comparison of macromolecular binding sites that integrates both structural and electrostatic properties. The vectors extend spherically from the center of the pocket, terminating at its surface to capture shape and electrostatic features in a multidimensional manner. Geometrically anchored, they enable a systematic comparison of binding sites across diverse systems. We applied this approach to cytochrome P450 (CYP) enzymes, analyzing over 600 human and…
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Taxonomy
TopicsPharmacogenetics and Drug Metabolism · Computational Drug Discovery Methods · Protein Structure and Dynamics