The Role of Hydrophobic Nodes in the Dynamics of Class A β-Lactamases
Class A β-lactamases are known for being able to rapidly gain broad spectrum catalytic efficiency against most β-lactamase inhibitor combinations as a result of elusively minor point mutations. The evolution in class A β-lactamases occurs through optimisation of their dynamic phenotypes at different...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-09-01
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| Series: | Frontiers in Microbiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmicb.2021.720991/full |
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| author | Edgar Olehnovics Junqi Yin Adrià Pérez Gianni De Fabritiis Gianni De Fabritiis Robert A. Bonomo Robert A. Bonomo Robert A. Bonomo Robert A. Bonomo Robert A. Bonomo Robert A. Bonomo Robert A. Bonomo Debsindhu Bhowmik Shozeb Haider |
| author_facet | Edgar Olehnovics Junqi Yin Adrià Pérez Gianni De Fabritiis Gianni De Fabritiis Robert A. Bonomo Robert A. Bonomo Robert A. Bonomo Robert A. Bonomo Robert A. Bonomo Robert A. Bonomo Robert A. Bonomo Debsindhu Bhowmik Shozeb Haider |
| author_sort | Edgar Olehnovics |
| collection | DOAJ |
| description | Class A β-lactamases are known for being able to rapidly gain broad spectrum catalytic efficiency against most β-lactamase inhibitor combinations as a result of elusively minor point mutations. The evolution in class A β-lactamases occurs through optimisation of their dynamic phenotypes at different timescales. At long-timescales, certain conformations are more catalytically permissive than others while at the short timescales, fine-grained optimisation of free energy barriers can improve efficiency in ligand processing by the active site. Free energy barriers, which define all coordinated movements, depend on the flexibility of the secondary structural elements. The most highly conserved residues in class A β-lactamases are hydrophobic nodes that stabilize the core. To assess how the stable hydrophobic core is linked to the structural dynamics of the active site, we carried out adaptively sampled molecular dynamics (MD) simulations in four representative class A β-lactamases (KPC-2, SME-1, TEM-1, and SHV-1). Using Markov State Models (MSM) and unsupervised deep learning, we show that the dynamics of the hydrophobic nodes is used as a metastable relay of kinetic information within the core and is coupled with the catalytically permissive conformation of the active site environment. Our results collectively demonstrate that the class A enzymes described here, share several important dynamic similarities and the hydrophobic nodes comprise of an informative set of dynamic variables in representative class A β-lactamases. |
| first_indexed | 2024-12-21T15:18:29Z |
| format | Article |
| id | doaj.art-207d9401f8e24b0391affe1a99d428c3 |
| institution | Directory Open Access Journal |
| issn | 1664-302X |
| language | English |
| last_indexed | 2024-12-21T15:18:29Z |
| publishDate | 2021-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Microbiology |
| spelling | doaj.art-207d9401f8e24b0391affe1a99d428c32022-12-21T18:59:06ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2021-09-011210.3389/fmicb.2021.720991720991The Role of Hydrophobic Nodes in the Dynamics of Class A β-LactamasesEdgar Olehnovics0Junqi Yin1Adrià Pérez2Gianni De Fabritiis3Gianni De Fabritiis4Robert A. Bonomo5Robert A. Bonomo6Robert A. Bonomo7Robert A. Bonomo8Robert A. Bonomo9Robert A. Bonomo10Robert A. Bonomo11Debsindhu Bhowmik12Shozeb Haider13Pharmaceutical and Biological Chemistry, University College London School of Pharmacy, London, United KingdomOak Ridge National Laboratory, National Center for Computational Sciences, Oak Ridge, TN, United StatesComputational Science Laboratory, Barcelona Biomedical Research Park, Universitat Pompeu Fabra, Barcelona, SpainComputational Science Laboratory, Barcelona Biomedical Research Park, Universitat Pompeu Fabra, Barcelona, SpainInstitució Catalana de Recerca i Estudis Avançats, Barcelona, SpainDepartment of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, OH, United StatesDepartment of Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH, United StatesDepartment of Biochemistry, Case Western Reserve University, Cleveland, OH, United StatesDepartment of Pharmacology, Case Western Reserve University, Cleveland, OH, United StatesDepartment of Proteomics and Bioinformatics, Case Western Reserve University, Cleveland, OH, United States0CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology (Case VA CARES), Cleveland, OH, United States1Veterans Affairs Northeast Ohio Healthcare System, Research Service, Cleveland, OH, United States2Computer Sciences and Engineering Division, Oak Ridge National Laboratory, Oak Ridge, TN, United StatesPharmaceutical and Biological Chemistry, University College London School of Pharmacy, London, United KingdomClass A β-lactamases are known for being able to rapidly gain broad spectrum catalytic efficiency against most β-lactamase inhibitor combinations as a result of elusively minor point mutations. The evolution in class A β-lactamases occurs through optimisation of their dynamic phenotypes at different timescales. At long-timescales, certain conformations are more catalytically permissive than others while at the short timescales, fine-grained optimisation of free energy barriers can improve efficiency in ligand processing by the active site. Free energy barriers, which define all coordinated movements, depend on the flexibility of the secondary structural elements. The most highly conserved residues in class A β-lactamases are hydrophobic nodes that stabilize the core. To assess how the stable hydrophobic core is linked to the structural dynamics of the active site, we carried out adaptively sampled molecular dynamics (MD) simulations in four representative class A β-lactamases (KPC-2, SME-1, TEM-1, and SHV-1). Using Markov State Models (MSM) and unsupervised deep learning, we show that the dynamics of the hydrophobic nodes is used as a metastable relay of kinetic information within the core and is coupled with the catalytically permissive conformation of the active site environment. Our results collectively demonstrate that the class A enzymes described here, share several important dynamic similarities and the hydrophobic nodes comprise of an informative set of dynamic variables in representative class A β-lactamases.https://www.frontiersin.org/articles/10.3389/fmicb.2021.720991/fullβ-lactamaseclass Ahydrophobic nodesMarkov state modeldeep learningmolecular dynamics |
| spellingShingle | Edgar Olehnovics Junqi Yin Adrià Pérez Gianni De Fabritiis Gianni De Fabritiis Robert A. Bonomo Robert A. Bonomo Robert A. Bonomo Robert A. Bonomo Robert A. Bonomo Robert A. Bonomo Robert A. Bonomo Debsindhu Bhowmik Shozeb Haider The Role of Hydrophobic Nodes in the Dynamics of Class A β-Lactamases Frontiers in Microbiology β-lactamase class A hydrophobic nodes Markov state model deep learning molecular dynamics |
| title | The Role of Hydrophobic Nodes in the Dynamics of Class A β-Lactamases |
| title_full | The Role of Hydrophobic Nodes in the Dynamics of Class A β-Lactamases |
| title_fullStr | The Role of Hydrophobic Nodes in the Dynamics of Class A β-Lactamases |
| title_full_unstemmed | The Role of Hydrophobic Nodes in the Dynamics of Class A β-Lactamases |
| title_short | The Role of Hydrophobic Nodes in the Dynamics of Class A β-Lactamases |
| title_sort | role of hydrophobic nodes in the dynamics of class a β lactamases |
| topic | β-lactamase class A hydrophobic nodes Markov state model deep learning molecular dynamics |
| url | https://www.frontiersin.org/articles/10.3389/fmicb.2021.720991/full |
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