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Characterizing Protease Specificity: How Many Substrates Do We Need?

Calculation of cleavage entropies allows to quantify, map and compare protease substrate specificity by an information entropy based approach. The metric intrinsically depends on the number of experimentally determined substrates (data points). Thus a statistical analysis of its numerical stability...

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Autores principales: Schauperl, Michael, Fuchs, Julian E., Waldner, Birgit J., Huber, Roland G., Kramer, Christian, Liedl, Klaus R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4641643/
https://www.ncbi.nlm.nih.gov/pubmed/26559682
http://dx.doi.org/10.1371/journal.pone.0142658
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author Schauperl, Michael
Fuchs, Julian E.
Waldner, Birgit J.
Huber, Roland G.
Kramer, Christian
Liedl, Klaus R.
author_facet Schauperl, Michael
Fuchs, Julian E.
Waldner, Birgit J.
Huber, Roland G.
Kramer, Christian
Liedl, Klaus R.
author_sort Schauperl, Michael
collection PubMed
description Calculation of cleavage entropies allows to quantify, map and compare protease substrate specificity by an information entropy based approach. The metric intrinsically depends on the number of experimentally determined substrates (data points). Thus a statistical analysis of its numerical stability is crucial to estimate the systematic error made by estimating specificity based on a limited number of substrates. In this contribution, we show the mathematical basis for estimating the uncertainty in cleavage entropies. Sets of cleavage entropies are calculated using experimental cleavage data and modeled extreme cases. By analyzing the underlying mathematics and applying statistical tools, a linear dependence of the metric in respect to 1/n was found. This allows us to extrapolate the values to an infinite number of samples and to estimate the errors. Analyzing the errors, a minimum number of 30 substrates was found to be necessary to characterize substrate specificity, in terms of amino acid variability, for a protease (S4-S4’) with an uncertainty of 5 percent. Therefore, we encourage experimental researchers in the protease field to record specificity profiles of novel proteases aiming to identify at least 30 peptide substrates of maximum sequence diversity. We expect a full characterization of protease specificity helpful to rationalize biological functions of proteases and to assist rational drug design.
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spelling pubmed-46416432015-11-18 Characterizing Protease Specificity: How Many Substrates Do We Need? Schauperl, Michael Fuchs, Julian E. Waldner, Birgit J. Huber, Roland G. Kramer, Christian Liedl, Klaus R. PLoS One Research Article Calculation of cleavage entropies allows to quantify, map and compare protease substrate specificity by an information entropy based approach. The metric intrinsically depends on the number of experimentally determined substrates (data points). Thus a statistical analysis of its numerical stability is crucial to estimate the systematic error made by estimating specificity based on a limited number of substrates. In this contribution, we show the mathematical basis for estimating the uncertainty in cleavage entropies. Sets of cleavage entropies are calculated using experimental cleavage data and modeled extreme cases. By analyzing the underlying mathematics and applying statistical tools, a linear dependence of the metric in respect to 1/n was found. This allows us to extrapolate the values to an infinite number of samples and to estimate the errors. Analyzing the errors, a minimum number of 30 substrates was found to be necessary to characterize substrate specificity, in terms of amino acid variability, for a protease (S4-S4’) with an uncertainty of 5 percent. Therefore, we encourage experimental researchers in the protease field to record specificity profiles of novel proteases aiming to identify at least 30 peptide substrates of maximum sequence diversity. We expect a full characterization of protease specificity helpful to rationalize biological functions of proteases and to assist rational drug design. Public Library of Science 2015-11-11 /pmc/articles/PMC4641643/ /pubmed/26559682 http://dx.doi.org/10.1371/journal.pone.0142658 Text en © 2015 Schauperl et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Schauperl, Michael
Fuchs, Julian E.
Waldner, Birgit J.
Huber, Roland G.
Kramer, Christian
Liedl, Klaus R.
Characterizing Protease Specificity: How Many Substrates Do We Need?
title Characterizing Protease Specificity: How Many Substrates Do We Need?
title_full Characterizing Protease Specificity: How Many Substrates Do We Need?
title_fullStr Characterizing Protease Specificity: How Many Substrates Do We Need?
title_full_unstemmed Characterizing Protease Specificity: How Many Substrates Do We Need?
title_short Characterizing Protease Specificity: How Many Substrates Do We Need?
title_sort characterizing protease specificity: how many substrates do we need?
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4641643/
https://www.ncbi.nlm.nih.gov/pubmed/26559682
http://dx.doi.org/10.1371/journal.pone.0142658
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