Polyphony: superposition independent methods for ensemble-based drug discovery

• Published in: BMC bioinformatics Vol. 15; no. 1; p. 324
• Main Authors: Pitt, William R, Montalvão, Rinaldo W, Blundell, Tom L
• Format: Journal Article
• Language: English
• Published: London BioMed Central 30.09.2014
• Subjects: Activation; Algorithms; Allosteric Site; Bioinformatics; Biomedical and Life Sciences; Computational Biology - methods; Computational Biology/Bioinformatics; Computer Appl. in Life Sciences; Computer simulation; Crystal structure; Crystallography, X-Ray; Cyclin-Dependent Kinase 2 - chemistry; Cyclin-Dependent Kinase 2 - metabolism; Drug Design; Drug Discovery - methods; Drugs; Kinases; Life Sciences; Ligands; Methodology; Methodology Article; Microarrays; Mitogen-Activated Protein Kinase 14 - chemistry; Mitogen-Activated Protein Kinase 14 - metabolism; Molecular Dynamics Simulation; Phosphorylation; Pocket; Protein Conformation; Proteins; Source code; Structural analysis; Root Mean Square Deviation; Backbone Conformation; Root Mean Square Fluctuation; Alignment Position; Hinge Region
• ISSN: 1471-2105; 1471-2105
• DOI: 10.1186/1471-2105-15-324

Background Structure-based drug design is an iterative process, following cycles of structural biology, computer-aided design, synthetic chemistry and bioassay. In favorable circumstances, this process can lead to the structures of hundreds of protein-ligand crystal structures. In addition, molecular dynamics simulations are increasingly being used to further explore the conformational landscape of these complexes. Currently, methods capable of the analysis of ensembles of crystal structures and MD trajectories are limited and usually rely upon least squares superposition of coordinates. Results Novel methodologies are described for the analysis of multiple structures of a protein. Statistical approaches that rely upon residue equivalence, but not superposition, are developed. Tasks that can be performed include the identification of hinge regions, allosteric conformational changes and transient binding sites. The approaches are tested on crystal structures of CDK2 and other CMGC protein kinases and a simulation of p38α. Known interaction - conformational change relationships are highlighted but also new ones are revealed. A transient but druggable allosteric pocket in CDK2 is predicted to occur under the CMGC insert. Furthermore, an evolutionarily-conserved conformational link from the location of this pocket, via the αEF-αF loop, to phosphorylation sites on the activation loop is discovered. Conclusions New methodologies are described and validated for the superimposition independent conformational analysis of large collections of structures or simulation snapshots of the same protein. The methodologies are encoded in a Python package called Polyphony, which is released as open source to accompany this paper [ http://wrpitt.bitbucket.org/polyphony/ ].