HydroPaCe: uma metodologia para análise de inibição cruzada em serino proteases através de centroides de regiões hidrofóbicas

Abstract

Interfaces of protein-protein interactions contain important information about molecular recognition. This work aims at the discovery of conserved patterns in this region. We believe it is essential to understand how substrates and inhibitors are bound and for predicting molecular binding. When an inhibitor binds to enzymes with different structures, sequences or mechanisms, we call this lack of specicity of Cross-Inhibition. The identication of variants is a dicult task for which traditional methods may fail. To understand how the cross-inhibition occurs, we model the problem and propose a methodology, whichwe call HydroPaCe(HydrofobicPatch Centroid) and we evaluate, through penalized recall metric - PRM, to detect preserved patterns. The hydrophobic atoms that belong to the interface were modeled as graphs of apolar interactions and hydrofobic connected regions or patches were computed and summarized by geometric centroids (HP-centroids), andtheir conservation is detected. We analyze two cases of cross-inhibition, one with the inhibitor Ovomovoid (5 non-redundant complexes) and another with the inhibitor Eglin C (4 non-redundant complexes). In addition, two families of serine proteases with single chain (apo-enzymes) were analyzed using projection of the interface technique: The Trypsin-like (35 non-redundant structures) and the Subtilisin-like (9 non-redundant structures). The patterns found in the interfaces of cross-inhibitions were found in most enzymes these families. We believe that our methodology achieves an appropriate level of abstraction toobtain invariant properties in cross-inhibition. We show examples in which HP-centroids successfully predicted enzymes that could be inhibited by the studied inhibitors according to BRENDA database. Finally, we provide all codes used in the methodological steps, aswell as tutorials and examples in www.dcc.ufmg.br/raquelcm/hydropace.