Underlying Thermodynamics of pH-Dependent Allostery

Understanding the effects of coupling protein protonation and conformational states is critical to the development of drugs targeting pH sensors and to the rational engineering of pH switches. In this work, we address this issue by performing a comprehensive study of the pH-regulated switch from the...

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Autores principales:	Di Russo, N.V., Martí, M.A., Roitberg, A.E.
Formato:	JOUR
Materias:	Amino acids Conformations Equilibrium constants Free energy Molecular biology pH pH sensors Proteins Protonation Thermodynamics Accurate estimation Conformational change Conformational equilibrium Conformational state Free energy landscape Molecular evolution pH-dependent activity Thermodynamic model pH effects hemoprotein nitrophorin recombinant protein saliva protein amino acid substitution biosynthesis chemistry genetics kinetics metabolism molecular dynamics protein tertiary structure thermodynamics Amino Acid Substitution Hemeproteins Hydrogen-Ion Concentration Kinetics Molecular Dynamics Simulation Protein Structure, Tertiary Recombinant Proteins Salivary Proteins and Peptides
Acceso en línea:	http://hdl.handle.net/20.500.12110/paper_15206106_v118_n45_p12818_DiRusso
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

id	todo:paper_15206106_v118_n45_p12818_DiRusso
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spelling	todo:paper_15206106_v118_n45_p12818_DiRusso2023-10-03T16:20:28Z Underlying Thermodynamics of pH-Dependent Allostery Di Russo, N.V. Martí, M.A. Roitberg, A.E. Amino acids Conformations Equilibrium constants Free energy Molecular biology pH pH sensors Proteins Protonation Thermodynamics Accurate estimation Conformational change Conformational equilibrium Conformational state Free energy landscape Molecular evolution pH-dependent activity Thermodynamic model pH effects hemoprotein nitrophorin recombinant protein saliva protein amino acid substitution biosynthesis chemistry genetics kinetics metabolism molecular dynamics pH protein tertiary structure thermodynamics Amino Acid Substitution Hemeproteins Hydrogen-Ion Concentration Kinetics Molecular Dynamics Simulation Protein Structure, Tertiary Recombinant Proteins Salivary Proteins and Peptides Thermodynamics Understanding the effects of coupling protein protonation and conformational states is critical to the development of drugs targeting pH sensors and to the rational engineering of pH switches. In this work, we address this issue by performing a comprehensive study of the pH-regulated switch from the closed to the open conformation in nitrophorin 4 (NP4) that determines its pH-dependent activity. Our calculations show that D30 is the only amino acid that has two significantly different pK<inf>a</inf>s in the open and closed conformations, confirming its critical role in regulating pH-dependent behavior. In addition, we describe the free-energy landscape of the conformational change as a function of pH, obtaining accurate estimations of free-energy barriers and equilibrium constants using different methods. The underlying thermodynamic model of the switch workings suggests the possibility of tuning the observed pK<inf>a</inf> only through the conformational equilibria, keeping the same conformation-specific pK<inf>a</inf>s, as evidenced by the proposed K125L mutant. Moreover, coupling between the protonation and conformational equilibria results in efficient regulation and pH-sensing around physiological pH values only for some combinations of protonation and conformational equilibrium constants, placing constraints on their possible values and leaving a narrow space for protein molecular evolution. The calculations and analysis presented here are of general applicability and provide a guide as to how more complex systems can be studied, offering insight into how pH-regulated allostery works of great value for designing drugs that target pH sensors and for rational engineering of pH switches beyond the common histidine trigger. © 2014 American Chemical Society. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_15206106_v118_n45_p12818_DiRusso
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic	Amino acids Conformations Equilibrium constants Free energy Molecular biology pH pH sensors Proteins Protonation Thermodynamics Accurate estimation Conformational change Conformational equilibrium Conformational state Free energy landscape Molecular evolution pH-dependent activity Thermodynamic model pH effects hemoprotein nitrophorin recombinant protein saliva protein amino acid substitution biosynthesis chemistry genetics kinetics metabolism molecular dynamics pH protein tertiary structure thermodynamics Amino Acid Substitution Hemeproteins Hydrogen-Ion Concentration Kinetics Molecular Dynamics Simulation Protein Structure, Tertiary Recombinant Proteins Salivary Proteins and Peptides Thermodynamics
spellingShingle	Amino acids Conformations Equilibrium constants Free energy Molecular biology pH pH sensors Proteins Protonation Thermodynamics Accurate estimation Conformational change Conformational equilibrium Conformational state Free energy landscape Molecular evolution pH-dependent activity Thermodynamic model pH effects hemoprotein nitrophorin recombinant protein saliva protein amino acid substitution biosynthesis chemistry genetics kinetics metabolism molecular dynamics pH protein tertiary structure thermodynamics Amino Acid Substitution Hemeproteins Hydrogen-Ion Concentration Kinetics Molecular Dynamics Simulation Protein Structure, Tertiary Recombinant Proteins Salivary Proteins and Peptides Thermodynamics Di Russo, N.V. Martí, M.A. Roitberg, A.E. Underlying Thermodynamics of pH-Dependent Allostery
topic_facet	Amino acids Conformations Equilibrium constants Free energy Molecular biology pH pH sensors Proteins Protonation Thermodynamics Accurate estimation Conformational change Conformational equilibrium Conformational state Free energy landscape Molecular evolution pH-dependent activity Thermodynamic model pH effects hemoprotein nitrophorin recombinant protein saliva protein amino acid substitution biosynthesis chemistry genetics kinetics metabolism molecular dynamics pH protein tertiary structure thermodynamics Amino Acid Substitution Hemeproteins Hydrogen-Ion Concentration Kinetics Molecular Dynamics Simulation Protein Structure, Tertiary Recombinant Proteins Salivary Proteins and Peptides Thermodynamics
description	Understanding the effects of coupling protein protonation and conformational states is critical to the development of drugs targeting pH sensors and to the rational engineering of pH switches. In this work, we address this issue by performing a comprehensive study of the pH-regulated switch from the closed to the open conformation in nitrophorin 4 (NP4) that determines its pH-dependent activity. Our calculations show that D30 is the only amino acid that has two significantly different pK<inf>a</inf>s in the open and closed conformations, confirming its critical role in regulating pH-dependent behavior. In addition, we describe the free-energy landscape of the conformational change as a function of pH, obtaining accurate estimations of free-energy barriers and equilibrium constants using different methods. The underlying thermodynamic model of the switch workings suggests the possibility of tuning the observed pK<inf>a</inf> only through the conformational equilibria, keeping the same conformation-specific pK<inf>a</inf>s, as evidenced by the proposed K125L mutant. Moreover, coupling between the protonation and conformational equilibria results in efficient regulation and pH-sensing around physiological pH values only for some combinations of protonation and conformational equilibrium constants, placing constraints on their possible values and leaving a narrow space for protein molecular evolution. The calculations and analysis presented here are of general applicability and provide a guide as to how more complex systems can be studied, offering insight into how pH-regulated allostery works of great value for designing drugs that target pH sensors and for rational engineering of pH switches beyond the common histidine trigger. © 2014 American Chemical Society.
format	JOUR
author	Di Russo, N.V. Martí, M.A. Roitberg, A.E.
author_facet	Di Russo, N.V. Martí, M.A. Roitberg, A.E.
author_sort	Di Russo, N.V.
title	Underlying Thermodynamics of pH-Dependent Allostery
title_short	Underlying Thermodynamics of pH-Dependent Allostery
title_full	Underlying Thermodynamics of pH-Dependent Allostery
title_fullStr	Underlying Thermodynamics of pH-Dependent Allostery
title_full_unstemmed	Underlying Thermodynamics of pH-Dependent Allostery
title_sort	underlying thermodynamics of ph-dependent allostery
url	http://hdl.handle.net/20.500.12110/paper_15206106_v118_n45_p12818_DiRusso
work_keys_str_mv	AT dirussonv underlyingthermodynamicsofphdependentallostery AT martima underlyingthermodynamicsofphdependentallostery AT roitbergae underlyingthermodynamicsofphdependentallostery
_version_	1807316699949563904

Underlying Thermodynamics of pH-Dependent Allostery

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