Mapping of ligand-binding cavities in proteins

C. David Andersson, Brian Y. Chen, Anna Linusson
2009 Proteins: Structure, Function, and Bioinformatics  
The complex interactions between proteins and small organic molecules (ligands) are intensively studied because they play key roles in biological processes and drug activities. Here, we present a novel approach to characterise and map the ligand-binding cavities of proteins without direct geometric comparison of structures, based on Principal Component Analysis of cavity properties (related mainly to size, polarity and charge). This approach can provide valuable information on the similarities,
more » ... and dissimilarities, of binding cavities due to mutations, between-species differences and flexibility upon ligand-binding. The presented results show that information on ligand-binding cavity variations can complement information on protein similarity obtained from sequence comparisons. The predictive aspect of the method is exemplified by successful predictions of serine proteases that were not included in the model construction. The presented strategy to compare ligand-binding cavities of related and unrelated proteins has many potential applications within protein and medicinal chemistry, for example in the characterisation and mapping of "orphan structures", selection of protein structures for docking studies in structurebased design and identification of proteins for selectivity screens in drug design programs. Table of proteins used in the study, list of descriptors included in the final PCA model, table of proteins used in the PCA clustering tree, information of the PCA of ligand features, correlation plots between ligand properties and ligand-binding cavity properties, tables of ligand descriptors and ligand PCA score values, statistical values and a SCREE-plot for the total ligand-binding cavity PCA, score plot including Eukaryotic proteases and prediction set B, score plot highlighting the TS proteins, PCA clustering tree containing all PDB code and information regarding the PLS-DA. This material is available free of charge via the Internet at Supporting Information Available:
doi:10.1002/prot.22655 pmid:20034113 pmcid:PMC2957484 fatcat:q7rjm37nefhlji3i7ljsisysdq