QM/MM free energy Simulations of an efficient Gluten Hydrolase (Kuma030) Implicate for a Reactant-State Based Protein-Design Strategy for General Acid/Base Catalysis

Abstract It is a grand attraction for contemporary biochemists to computationally design enzymes for novel chemical transformation or improved catalytic efficiency. Rosetta by Baker et al. is no doubt the leading software in the protein design society. Generally, optimization of the transition state...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Xia Wang, Ruirui Li, Wenchao Cui, Qiang Li, Jianzhuang Yao
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/7d15b7cb8c4f402d961d99953e8c700e
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:7d15b7cb8c4f402d961d99953e8c700e
record_format	dspace
spelling	oai:doaj.org-article:7d15b7cb8c4f402d961d99953e8c700e2021-12-02T11:40:47ZQM/MM free energy Simulations of an efficient Gluten Hydrolase (Kuma030) Implicate for a Reactant-State Based Protein-Design Strategy for General Acid/Base Catalysis10.1038/s41598-018-25471-z2045-2322https://doaj.org/article/7d15b7cb8c4f402d961d99953e8c700e2018-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-25471-zhttps://doaj.org/toc/2045-2322Abstract It is a grand attraction for contemporary biochemists to computationally design enzymes for novel chemical transformation or improved catalytic efficiency. Rosetta by Baker et al. is no doubt the leading software in the protein design society. Generally, optimization of the transition state (TS) is part of the Rosetta’s protocol to enhance the catalytic efficiency of target enzymes, since TS stabilization is the determining factor for catalytic efficiency based on the TS theory (TST). However, it is confusing that optimization of the reactant state (RS) also results in significant improvement of catalytic efficiency in some cases, such as design of gluten hydrolase (Kuma030). Therefore, it is interesting to uncover underlying reason why a better binding in the RS leading to an increased k cat . In this study, the combined quantum mechanical/molecular mechanical (QM/MM) molecular dynamics (MD) and free energy (PMF) simulations, pK a calculation, and the statistical analysis such as the ANOVA test were carried out to shed light on the interesting but elusive question. By integration of our computational results and general acid/base theory, we answered the question why optimization of RS stabilization leads to a better TS stabilization in the general acid/base catalysis. In addition, a new and simplified protein-design strategy is proposed for the general acid/base catalysis. The idea, that application of traditional well-defined enzyme mechanism to protein design strategy, would be a great help for methodology development of protein design.Xia WangRuirui LiWenchao CuiQiang LiJianzhuang YaoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-11 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Xia Wang Ruirui Li Wenchao Cui Qiang Li Jianzhuang Yao QM/MM free energy Simulations of an efficient Gluten Hydrolase (Kuma030) Implicate for a Reactant-State Based Protein-Design Strategy for General Acid/Base Catalysis
description	Abstract It is a grand attraction for contemporary biochemists to computationally design enzymes for novel chemical transformation or improved catalytic efficiency. Rosetta by Baker et al. is no doubt the leading software in the protein design society. Generally, optimization of the transition state (TS) is part of the Rosetta’s protocol to enhance the catalytic efficiency of target enzymes, since TS stabilization is the determining factor for catalytic efficiency based on the TS theory (TST). However, it is confusing that optimization of the reactant state (RS) also results in significant improvement of catalytic efficiency in some cases, such as design of gluten hydrolase (Kuma030). Therefore, it is interesting to uncover underlying reason why a better binding in the RS leading to an increased k cat . In this study, the combined quantum mechanical/molecular mechanical (QM/MM) molecular dynamics (MD) and free energy (PMF) simulations, pK a calculation, and the statistical analysis such as the ANOVA test were carried out to shed light on the interesting but elusive question. By integration of our computational results and general acid/base theory, we answered the question why optimization of RS stabilization leads to a better TS stabilization in the general acid/base catalysis. In addition, a new and simplified protein-design strategy is proposed for the general acid/base catalysis. The idea, that application of traditional well-defined enzyme mechanism to protein design strategy, would be a great help for methodology development of protein design.
format	article
author	Xia Wang Ruirui Li Wenchao Cui Qiang Li Jianzhuang Yao
author_facet	Xia Wang Ruirui Li Wenchao Cui Qiang Li Jianzhuang Yao
author_sort	Xia Wang
title	QM/MM free energy Simulations of an efficient Gluten Hydrolase (Kuma030) Implicate for a Reactant-State Based Protein-Design Strategy for General Acid/Base Catalysis
title_short	QM/MM free energy Simulations of an efficient Gluten Hydrolase (Kuma030) Implicate for a Reactant-State Based Protein-Design Strategy for General Acid/Base Catalysis
title_full	QM/MM free energy Simulations of an efficient Gluten Hydrolase (Kuma030) Implicate for a Reactant-State Based Protein-Design Strategy for General Acid/Base Catalysis
title_fullStr	QM/MM free energy Simulations of an efficient Gluten Hydrolase (Kuma030) Implicate for a Reactant-State Based Protein-Design Strategy for General Acid/Base Catalysis
title_full_unstemmed	QM/MM free energy Simulations of an efficient Gluten Hydrolase (Kuma030) Implicate for a Reactant-State Based Protein-Design Strategy for General Acid/Base Catalysis
title_sort	qm/mm free energy simulations of an efficient gluten hydrolase (kuma030) implicate for a reactant-state based protein-design strategy for general acid/base catalysis
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/7d15b7cb8c4f402d961d99953e8c700e
work_keys_str_mv	AT xiawang qmmmfreeenergysimulationsofanefficientglutenhydrolasekuma030implicateforareactantstatebasedproteindesignstrategyforgeneralacidbasecatalysis AT ruiruili qmmmfreeenergysimulationsofanefficientglutenhydrolasekuma030implicateforareactantstatebasedproteindesignstrategyforgeneralacidbasecatalysis AT wenchaocui qmmmfreeenergysimulationsofanefficientglutenhydrolasekuma030implicateforareactantstatebasedproteindesignstrategyforgeneralacidbasecatalysis AT qiangli qmmmfreeenergysimulationsofanefficientglutenhydrolasekuma030implicateforareactantstatebasedproteindesignstrategyforgeneralacidbasecatalysis AT jianzhuangyao qmmmfreeenergysimulationsofanefficientglutenhydrolasekuma030implicateforareactantstatebasedproteindesignstrategyforgeneralacidbasecatalysis
_version_	1718395524914085888

QM/MM free energy Simulations of an efficient Gluten Hydrolase (Kuma030) Implicate for a Reactant-State Based Protein-Design Strategy for General Acid/Base Catalysis

Ejemplares similares