Molecular Dynamics Simulations of Ground and Transition States for the SN2 Displacement of Cl-from 1,2-Dichloroethane at the Active Site ofXanthobacter autotrophicusHaloalkane Dehalogenase†

1998 ◽  
Vol 120 (23) ◽  
pp. 5611-5621 ◽  
Author(s):  
Felice C. Lightstone ◽  
Ya-Jun Zheng ◽  
Thomas C. Bruice
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Active Site ◽  
Transition States ◽  
Dynamics Simulations

scholarly journals Exploiting correlated molecular-dynamics networks to counteract enzyme activity–stability trade-off

2018 ◽  
Vol 115 (52) ◽  
pp. E12192-E12200 ◽  
Author(s):  
Haoran Yu ◽  
Paul A. Dalby
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Active Site ◽  
Dynamic Networks ◽  
Aromatic Aldehydes ◽  
Active Site Residues ◽  
Trade Off ◽  
Highly Correlated ◽  
Dynamics Simulations ◽  
The Impact

The directed evolution of enzymes for improved activity or substrate specificity commonly leads to a trade-off in stability. We have identified an activity–stability trade-off and a loss in unfolding cooperativity for a variant (3M) of Escherichia coli transketolase (TK) engineered to accept aromatic substrates. Molecular dynamics simulations of 3M revealed increased flexibility in several interconnected active-site regions that also form part of the dimer interface. Mutating the newly flexible active-site residues to regain stability risked losing the new activity. We hypothesized that stabilizing mutations could be targeted to residues outside of the active site, whose dynamics were correlated with the newly flexible active-site residues. We previously stabilized WT TK by targeting mutations to highly flexible regions. These regions were much less flexible in 3M and would not have been selected a priori as targets using the same strategy based on flexibility alone. However, their dynamics were highly correlated with the newly flexible active-site regions of 3M. Introducing the previous mutations into 3M reestablished the WT level of stability and unfolding cooperativity, giving a 10.8-fold improved half-life at 55 °C, and increased midpoint and aggregation onset temperatures by 3 °C and 4.3 °C, respectively. Even the activity toward aromatic aldehydes increased up to threefold. Molecular dynamics simulations confirmed that the mutations rigidified the active-site via the correlated network. This work provides insights into the impact of rigidifying mutations within highly correlated dynamic networks that could also be useful for developing improved computational protein engineering strategies.

Active site gate of M32 carboxypeptidases illuminated by crystal structure and molecular dynamics simulations

2017 ◽  
Vol 1865 (11) ◽  
pp. 1406-1415 ◽  
Author(s):  
Bhaskar Sharma ◽  
Sahayog N. Jamdar ◽  
Biplab Ghosh ◽  
Pooja Yadav ◽  
Ashwani Kumar ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Active Site ◽  
Dynamics Simulations

scholarly journals IDENTIFICATION OF POTENTIAL SALMONELLA TYPHI BETA-LACTAMASE TEM 1 INHIBITORS USING PEPTIDOMIMETICS, VIRTUAL SCREENING, AND MOLECULAR DYNAMICS SIMULATIONS

2018 ◽  
Vol 10 (1) ◽  
pp. 91
Author(s):  
Rakesh K. R. Pandit ◽  
Dinesh Gupta ◽  
Tapan K. Mukherjee
Keyword(s):  
Molecular Dynamics ◽  
Antibiotic Resistance ◽  
Virtual Screening ◽  
Molecular Dynamics Simulations ◽  
Active Site ◽  
Beta Lactamase ◽  
Ramachandran Plot ◽  
Small Peptide ◽  
In Silico Docking ◽  
Dynamics Simulations

Objective: The purpose of this study was to identify a potential peptidomimetic S. typhi Beta-lactamase TEM 1 inhibitor to tackle the antibiotic resistance among S. typhi.Methods: The potential peptidomimetic inhibitor was identified by in silico docking of the small peptide WFRKQLKW with S. typhi Beta-lactamase TEM 1. The 3D coordinate geometry of the residues of small peptide interacting with the active site of the receptor was generated and mimics were identified using PEP: MMs: MIMIC server. All the identified mimics were docked at the active site of the receptor using Autodock 4.2 and the best-docked complex was selected on the basis of binding energy and number of H-bonds. The complex was then subjected to molecular dynamics simulations of 30 ns using AMBER 12 software package. The stereochemical stability of the Beta-lactamase TEM 1-WFRKQLKW complex was estimated with the help of Ramachandran plot using PROCHECK tool.Results: In the present study, a new potential peptidomimetic inhibitor (ZINC05839264) of Beta-lactamase TEM 1 has been identified based on antimicrobial peptide WFRKQLKW by virtual screening of the MMsINC database. The docking and molecular simulation studies revealed that the mimic binds more tightly to the active site of the receptor than the peptide. The Ramachandran plot also shows that the Beta-lactamase TEM 1-mimic complex is stereo chemically more stable than Beta-lactamase TEM 1-WFRKQLKW complex as more number of residues (93.6%) are falling under the core region of the plot in case of the former.Conclusion: The study shows that the peptidomimetic compound can act as a potential inhibitor of S. typhi Beta-lactamase TEM 1 and further it can be developed into more effective therapeutic to tackle the problem of antibiotic resistance.

Reactive Conformation of the Active Site in the Hairpin Ribozyme Achieved by Molecular Dynamics Simulations with ε/ζ Force Field Reparametrizations

2015 ◽  
Vol 119 (11) ◽  
pp. 4220-4229 ◽  
Author(s):  
Vojtěch Mlýnský ◽  
Petra Kührová ◽  
Marie Zgarbová ◽  
Petr Jurečka ◽  
Nils G. Walter ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Force Field ◽  
Molecular Dynamics Simulations ◽  
Active Site ◽  
Hairpin Ribozyme ◽  
Dynamics Simulations
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