Underlying Thermodynamics of pH-Dependent Allostery

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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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Autor principal: Di Russo, N.V
Otros Autores: Martí, M.A, Roitberg, A.E
Formato: Capítulo de libro
Lenguaje:Inglés
Publicado: American Chemical Society 2014
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Biblioteca Central Dr. Luis F. Leloir (FCEN) de Universidad de Buenos Aires
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024 7 |2 scopus  |a 2-s2.0-84927558563 
024 7 |2 cas  |a Hemeproteins; nitrophorin; Recombinant Proteins; Salivary Proteins and Peptides 
040 |a Scopus  |b spa  |c AR-BaUEN  |d AR-BaUEN 
030 |a JPCBF 
100 1 |a Di Russo, N.V. 
245 1 0 |a Underlying Thermodynamics of pH-Dependent Allostery 
260 |b American Chemical Society  |c 2014 
270 1 0 |m Roitberg, A.E.; Quantum Theory Project, Department of Chemistry, University of FloridaUnited States 
506 |2 openaire  |e Política editorial 
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520 3 |a 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.  |l eng 
536 |a Detalles de la financiación: National Stroke Foundation, NSF, OCI 07-25070 
536 |a Detalles de la financiación: Petroleum Research Atlantic Canada, PRAC, OCI-1036208 
536 |a Detalles de la financiación: National Stroke Foundation, NSF, OCI-1147910 
536 |a Detalles de la financiación: Ministerio de Ciencia, Tecnología e Innovación Productiva, MINCyT, PICT-2010-416 
593 |a Quantum Theory Project, Department of Chemistry, University of Florida, Gainesville, FL 32611, United States 
593 |a Departamento de Química Inorgánica, Analítica y Química Física/INQUIMAE-CONICET, Universidad de Buenos Aires, Buenos Aires, C1428EGA, Argentina 
690 1 0 |a AMINO ACIDS 
690 1 0 |a CONFORMATIONS 
690 1 0 |a EQUILIBRIUM CONSTANTS 
690 1 0 |a FREE ENERGY 
690 1 0 |a MOLECULAR BIOLOGY 
690 1 0 |a PH SENSORS 
690 1 0 |a PROTEINS 
690 1 0 |a PROTONATION 
690 1 0 |a THERMODYNAMICS 
690 1 0 |a ACCURATE ESTIMATION 
690 1 0 |a CONFORMATIONAL CHANGE 
690 1 0 |a CONFORMATIONAL EQUILIBRIUM 
690 1 0 |a CONFORMATIONAL STATE 
690 1 0 |a FREE ENERGY LANDSCAPE 
690 1 0 |a MOLECULAR EVOLUTION 
690 1 0 |a PH-DEPENDENT ACTIVITY 
690 1 0 |a THERMODYNAMIC MODEL 
690 1 0 |a PH EFFECTS 
690 1 0 |a HEMOPROTEIN 
690 1 0 |a NITROPHORIN 
690 1 0 |a RECOMBINANT PROTEIN 
690 1 0 |a SALIVA PROTEIN 
690 1 0 |a AMINO ACID SUBSTITUTION 
690 1 0 |a BIOSYNTHESIS 
690 1 0 |a CHEMISTRY 
690 1 0 |a GENETICS 
690 1 0 |a KINETICS 
690 1 0 |a METABOLISM 
690 1 0 |a MOLECULAR DYNAMICS 
690 1 0 |a PROTEIN TERTIARY STRUCTURE 
690 1 0 |a THERMODYNAMICS 
690 1 0 |a AMINO ACID SUBSTITUTION 
690 1 0 |a HEMEPROTEINS 
690 1 0 |a HYDROGEN-ION CONCENTRATION 
690 1 0 |a KINETICS 
690 1 0 |a MOLECULAR DYNAMICS SIMULATION 
690 1 0 |a PROTEIN STRUCTURE, TERTIARY 
690 1 0 |a RECOMBINANT PROTEINS 
690 1 0 |a SALIVARY PROTEINS AND PEPTIDES 
690 1 0 |a THERMODYNAMICS 
650 1 7 |2 spines  |a PH 
650 1 7 |2 spines  |a PH 
700 1 |a Martí, M.A. 
700 1 |a Roitberg, A.E. 
773 0 |d American Chemical Society, 2014  |g v. 118  |h pp. 12818-12826  |k n. 45  |p J Phys Chem B  |x 15206106  |w (AR-BaUEN)CENRE-5879  |t Journal of Physical Chemistry B 
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856 4 0 |u https://doi.org/10.1021/jp507971v  |y DOI 
856 4 0 |u https://hdl.handle.net/20.500.12110/paper_15206106_v118_n45_p12818_DiRusso  |y Handle 
856 4 0 |u https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_15206106_v118_n45_p12818_DiRusso  |y Registro en la Biblioteca Digital 
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