Cleavage Entropy as Quantitative Measure of Protease Specificity

Abstract

A purely information theory-guided approach to quantitatively characterize protease specificity is established. We calculate an entropy value for each protease subpocket based on sequences of cleaved substrates extracted from the MEROPS database. We compare our results with known subpocket specificity profiles for individual proteases and protease groups (e.g. serine proteases, metallo proteases) and reflect them quantitatively. Summation of subpocket-wise cleavage entropy contributions yields a measure for overall protease substrate specificity. This total cleavage entropy allows ranking of different proteases with respect to their specificity, separating unspecific digestive enzymes showing high total cleavage entropy from specific proteases involved in signaling cascades. The development of a quantitative cleavage entropy score allows an unbiased comparison of subpocket-wise and overall protease specificity. Thus, it enables assessment of relative importance of physicochemical and structural descriptors in protease recognition. We present an exemplary application of cleavage entropy in tracing substrate specificity in protease evolution. This highlights the wide range of substrate promiscuity within homologue proteases and hence the heavy impact of a limited number of mutations on individual substrate specificity.

Promiscuous and specific recognition among ephrins and Eph receptors

“…First we analyze the co-evolution entropy of EphA4 ephrin-A2 and EphA4 ephrin-B2 complexes. Using ‘cleavage entropy’ as a quantitative measure of protease specificity [38], we calculate the specificity. Using 0.5 as stringent specificity, several anchoring residues in EphA4 are highly specific.…”

“…The protein sequence entropy analysis was performed as described by Fuchs et al [38] and Shen et al [39]. The entropy of each residue in the homologous families of the Eph receptor ligand binding domain and eprhin ligand used in co-evolution analysis was calculated.…”

Effects of Fenton Pre‐Treatment on Waste Activated Sludge Properties

“…With an increasingly accurate description of protein dynamics, its role in biomolecular recognition processes can be studied, thereby allowing pharmaceutically relevant properties like binding specificity89 or binding kinetics90 including allosteric mechanisms91 to be probed. On the other hand, integration of innovative data sources from emerging “omics” fields such as proteomics,92 metabonomics/metabolomics,93 or lipidomics94 will allow the capture of novel biological properties which have limited or no direct chemical leads to their mechanism and function.…”

The Proteasix Ontology

“…Proteases have a wide spectrum of specificity [1]. The human genome encodes over 550 different proteases, participating in many different biological processes, including protein degradation, immunity response, regeneration or cell division and are involved in diseases such as cancer, inflammation and cardiovascular disease [2, 3].…”