Efficient calculation of enzyme reaction free energy profiles using a hybrid differential relaxation algorithm: Application to mycobacterial zinc hydrolases
Determination of the free energy profile for an enzyme reaction mechanism is of primordial relevance, paving the way for our understanding of the enzyme's catalytic power at the molecular level. Although hybrid, mostly DFT-based, QM/MM methods have been extensively applied to this type of studi...
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todo:paper_18761623_v100_n_p33_Romero2023-10-03T16:34:16Z Efficient calculation of enzyme reaction free energy profiles using a hybrid differential relaxation algorithm: Application to mycobacterial zinc hydrolases Romero, J.M. Martin, M. Ramirez, C.L. Dumas, V.G. Marti, M.A. Karabencheva-Christova T. Free energy HyDRA Jarzynski's relationship M. tuberculosis MshB QM/MM Rv1170 Rv3717 Zn hydrolases amidase amide carbonyl derivative hydrolase hydroxide MA amidase MshB enzyme unclassified drug zinc ion amidase bacterial protein divalent cation n acetylmuramoylalanine amidase N-acetyl-1-D-inosityl-2-amino-2-deoxy-alpha-D-glucopyranoside deacetylase proton water zinc algorithm catalysis Conference Paper crystal structure enzyme analysis human Mycobacterium tuberculosis nonhuman priority journal proton transport reaction analysis tuberculosis algorithm biocatalysis chemistry enzymology molecular dynamics Mycobacterium tuberculosis protein secondary structure protein tertiary structure quantum theory species difference thermodynamics Algorithms Amidohydrolases Bacterial Proteins Biocatalysis Cations, Divalent Humans Molecular Dynamics Simulation Mycobacterium tuberculosis N-Acetylmuramoyl-L-alanine Amidase Protein Structure, Secondary Protein Structure, Tertiary Protons Quantum Theory Species Specificity Thermodynamics Water Zinc Determination of the free energy profile for an enzyme reaction mechanism is of primordial relevance, paving the way for our understanding of the enzyme's catalytic power at the molecular level. Although hybrid, mostly DFT-based, QM/MM methods have been extensively applied to this type of studies, achieving accurate and statistically converged results at a moderate computational cost is still an open challenge. Recently, we have shown that accurate results can be achieved in less computational time, combining Jarzynski's relationship with a hybrid differential relaxation algorithm (HyDRA), which allows partial relaxation of the solvent during the nonequilibrium steering of the reaction. In this work, we have applied this strategy to study two mycobacterial zinc hydrolases. Mycobacterium tuberculosis infections are still a worldwide problem and thus characterization and validation of new drug targets is an intense field of research. Among possible drug targets, recently two essential zinc hydrolases, MshB (Rv1170) and MA-amidase (Rv3717), have been proposed and structurally characterized. Although possible mechanisms have been proposed by analogy to the widely studied human Zn hydrolases, several key issues, particularly those related to Zn coordination sphere and its role in catalysis, remained unanswered. Our results show that mycobacterial Zn hydrolases share a basic two-step mechanism. First, the attacking water becomes deprotonated by the conserved base and establishes the new C-O bond leading to a tetrahedral intermediate. The intermediate requires moderate reorganization to allow for proton transfer to the amide N and C-N bond breaking to occur in the second step. Zn ion plays a key role in stabilizing the tetrahedral intermediate and balancing the negative charge of the substrate during hydroxide ion attack. Finally, comparative analysis of other Zn hydrolases points to a convergent mechanistic evolution. © 2015 Elsevier Inc. All rights reserved. Fil:Ramirez, C.L. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Dumas, V.G. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Marti, M.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. SER info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_18761623_v100_n_p33_Romero |
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Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
Free energy HyDRA Jarzynski's relationship M. tuberculosis MshB QM/MM Rv1170 Rv3717 Zn hydrolases amidase amide carbonyl derivative hydrolase hydroxide MA amidase MshB enzyme unclassified drug zinc ion amidase bacterial protein divalent cation n acetylmuramoylalanine amidase N-acetyl-1-D-inosityl-2-amino-2-deoxy-alpha-D-glucopyranoside deacetylase proton water zinc algorithm catalysis Conference Paper crystal structure enzyme analysis human Mycobacterium tuberculosis nonhuman priority journal proton transport reaction analysis tuberculosis algorithm biocatalysis chemistry enzymology molecular dynamics Mycobacterium tuberculosis protein secondary structure protein tertiary structure quantum theory species difference thermodynamics Algorithms Amidohydrolases Bacterial Proteins Biocatalysis Cations, Divalent Humans Molecular Dynamics Simulation Mycobacterium tuberculosis N-Acetylmuramoyl-L-alanine Amidase Protein Structure, Secondary Protein Structure, Tertiary Protons Quantum Theory Species Specificity Thermodynamics Water Zinc |
| spellingShingle |
Free energy HyDRA Jarzynski's relationship M. tuberculosis MshB QM/MM Rv1170 Rv3717 Zn hydrolases amidase amide carbonyl derivative hydrolase hydroxide MA amidase MshB enzyme unclassified drug zinc ion amidase bacterial protein divalent cation n acetylmuramoylalanine amidase N-acetyl-1-D-inosityl-2-amino-2-deoxy-alpha-D-glucopyranoside deacetylase proton water zinc algorithm catalysis Conference Paper crystal structure enzyme analysis human Mycobacterium tuberculosis nonhuman priority journal proton transport reaction analysis tuberculosis algorithm biocatalysis chemistry enzymology molecular dynamics Mycobacterium tuberculosis protein secondary structure protein tertiary structure quantum theory species difference thermodynamics Algorithms Amidohydrolases Bacterial Proteins Biocatalysis Cations, Divalent Humans Molecular Dynamics Simulation Mycobacterium tuberculosis N-Acetylmuramoyl-L-alanine Amidase Protein Structure, Secondary Protein Structure, Tertiary Protons Quantum Theory Species Specificity Thermodynamics Water Zinc Romero, J.M. Martin, M. Ramirez, C.L. Dumas, V.G. Marti, M.A. Karabencheva-Christova T. Efficient calculation of enzyme reaction free energy profiles using a hybrid differential relaxation algorithm: Application to mycobacterial zinc hydrolases |
| topic_facet |
Free energy HyDRA Jarzynski's relationship M. tuberculosis MshB QM/MM Rv1170 Rv3717 Zn hydrolases amidase amide carbonyl derivative hydrolase hydroxide MA amidase MshB enzyme unclassified drug zinc ion amidase bacterial protein divalent cation n acetylmuramoylalanine amidase N-acetyl-1-D-inosityl-2-amino-2-deoxy-alpha-D-glucopyranoside deacetylase proton water zinc algorithm catalysis Conference Paper crystal structure enzyme analysis human Mycobacterium tuberculosis nonhuman priority journal proton transport reaction analysis tuberculosis algorithm biocatalysis chemistry enzymology molecular dynamics Mycobacterium tuberculosis protein secondary structure protein tertiary structure quantum theory species difference thermodynamics Algorithms Amidohydrolases Bacterial Proteins Biocatalysis Cations, Divalent Humans Molecular Dynamics Simulation Mycobacterium tuberculosis N-Acetylmuramoyl-L-alanine Amidase Protein Structure, Secondary Protein Structure, Tertiary Protons Quantum Theory Species Specificity Thermodynamics Water Zinc |
| description |
Determination of the free energy profile for an enzyme reaction mechanism is of primordial relevance, paving the way for our understanding of the enzyme's catalytic power at the molecular level. Although hybrid, mostly DFT-based, QM/MM methods have been extensively applied to this type of studies, achieving accurate and statistically converged results at a moderate computational cost is still an open challenge. Recently, we have shown that accurate results can be achieved in less computational time, combining Jarzynski's relationship with a hybrid differential relaxation algorithm (HyDRA), which allows partial relaxation of the solvent during the nonequilibrium steering of the reaction. In this work, we have applied this strategy to study two mycobacterial zinc hydrolases. Mycobacterium tuberculosis infections are still a worldwide problem and thus characterization and validation of new drug targets is an intense field of research. Among possible drug targets, recently two essential zinc hydrolases, MshB (Rv1170) and MA-amidase (Rv3717), have been proposed and structurally characterized. Although possible mechanisms have been proposed by analogy to the widely studied human Zn hydrolases, several key issues, particularly those related to Zn coordination sphere and its role in catalysis, remained unanswered. Our results show that mycobacterial Zn hydrolases share a basic two-step mechanism. First, the attacking water becomes deprotonated by the conserved base and establishes the new C-O bond leading to a tetrahedral intermediate. The intermediate requires moderate reorganization to allow for proton transfer to the amide N and C-N bond breaking to occur in the second step. Zn ion plays a key role in stabilizing the tetrahedral intermediate and balancing the negative charge of the substrate during hydroxide ion attack. Finally, comparative analysis of other Zn hydrolases points to a convergent mechanistic evolution. © 2015 Elsevier Inc. All rights reserved. |
| format |
SER |
| author |
Romero, J.M. Martin, M. Ramirez, C.L. Dumas, V.G. Marti, M.A. Karabencheva-Christova T. |
| author_facet |
Romero, J.M. Martin, M. Ramirez, C.L. Dumas, V.G. Marti, M.A. Karabencheva-Christova T. |
| author_sort |
Romero, J.M. |
| title |
Efficient calculation of enzyme reaction free energy profiles using a hybrid differential relaxation algorithm: Application to mycobacterial zinc hydrolases |
| title_short |
Efficient calculation of enzyme reaction free energy profiles using a hybrid differential relaxation algorithm: Application to mycobacterial zinc hydrolases |
| title_full |
Efficient calculation of enzyme reaction free energy profiles using a hybrid differential relaxation algorithm: Application to mycobacterial zinc hydrolases |
| title_fullStr |
Efficient calculation of enzyme reaction free energy profiles using a hybrid differential relaxation algorithm: Application to mycobacterial zinc hydrolases |
| title_full_unstemmed |
Efficient calculation of enzyme reaction free energy profiles using a hybrid differential relaxation algorithm: Application to mycobacterial zinc hydrolases |
| title_sort |
efficient calculation of enzyme reaction free energy profiles using a hybrid differential relaxation algorithm: application to mycobacterial zinc hydrolases |
| url |
http://hdl.handle.net/20.500.12110/paper_18761623_v100_n_p33_Romero |
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