Enzymatic Catalysis of the Peptidyl—Prolyl Bond Rotation: Are Transition State Formation and Enzyme Dynamics Directly Linked?

ChemInform ◽  
2003 ◽  
Vol 34 (18) ◽  
Author(s):  
Joerg Fanghaenel
Keyword(s):  
Transition State ◽  
State Formation ◽  
Enzymatic Catalysis ◽  
Enzyme Dynamics ◽  
Bond Rotation

scholarly journals Characterization of the Transition State of Functional Enzyme Dynamics

2006 ◽  
Vol 128 (24) ◽  
pp. 7724-7725 ◽  
Author(s):  
Evgenii L. Kovrigin ◽  
J. Patrick Loria
Keyword(s):  
Transition State ◽  
Enzyme Dynamics

What happens to formamide during C—N bond rotation? Atomic and molecular energetics and molecular reactivity as a function of internal rotation

1993 ◽  
Vol 71 (6) ◽  
pp. 872-879 ◽  
Author(s):  
Keith E. Laidig ◽  
Lynn M. Cameron
Keyword(s):  
Electric Fields ◽  
Molecular Level ◽  
Enzymatic Catalysis ◽  
Nucleophilic Attack ◽  
Torsional Angle ◽  
Carbonyl Carbon ◽  
Electrophilic Attack ◽  
Bond Rotation ◽  
Planar Conformation ◽  
Molecular Reactivity

We investigate the energetics of rotation about the C—N bond in formamide at the molecular and atomic levels using the HF/6-31G**//HF/6-31G** level of theory. At the molecular level, the barrier to rotation results from a decrease in overall attractive energies upon rotation away from the planar conformation, primarily due to the lengthening of the C—N bond. At the atomic level, the barrier is due to the loss in interatomic attraction between the nitrogen and its bonded neighbors. We investigate the susceptibility of formamide to electrophilic attack at nitrogen and oxygen as well as nucleophilic attack at carbonyl carbon as a function of C—N bond rotation using the Laplacian model of reactivity. The model predicts the susceptibility to nucleophilic attack at carbonyl carbon to reach a maximum with a O—C—N—H torsional angle of 60°. As a mimic of solvent fields, we investigate the effect of solvation upon these predictions with the application of homogeneous electric fields. This geometry–reactivity relationship is related to proposed models of activation in the enzymatic catalysis of peptides.

scholarly journals A Threonine on the Active Site Loop Controls Transition State Formation inEscherichia coliRespiratory Complex II

2008 ◽  
Vol 283 (22) ◽  
pp. 15460-15468 ◽  
Author(s):  
Thomas M. Tomasiak ◽  
Elena Maklashina ◽  
Gary Cecchini ◽  
Tina M. Iverson
Keyword(s):  
Transition State ◽  
State Formation ◽  
Active Site ◽  
Complex Ii

scholarly journals Microsecond Timescale Simulations at the Transition State of PmHMGR Predict Remote Allosteric Residues

2019 ◽  
Author(s):  
Taylor Quinn ◽  
Calvin N. Steussy ◽  
Brandon E. Haines ◽  
Jinping Lei ◽  
Wei Wang ◽  
...  
Keyword(s):  
Transition State ◽  
Molecular Mechanics ◽  
Conformational Changes ◽  
Enzymatic Catalysis ◽  
Dynamic Effect ◽  
Md Simulations ◽  
Site Directed Mutagenesis ◽  
Pseudomonas Mevalonii ◽  
Remote Residues ◽  
Coa Reductase

<p>Understanding the mechanisms of enzymatic catalysis requires a detailed understanding of the complex interplay of structure and dynamics of large systems that is a challenge for both experimental and computational approaches. QM/MM methods have been extensively used to study these reactions, but the difficulties arising from the hybrid treatment of the system are well documented. More importantly, the computational demands of QM/MM simulations mean that the dynamics of the reaction can only be considered on a timescale of nanoseconds even though the conformational changes needed to react the catalytically active state happen on a much slower timescale. Here we demonstrate an alternative approach that uses transition state force fields (TSFFs) derived by the quantum-guided molecular mechanics (Q2MM) method that provides a consistent treatment of the entire system at the classical molecular mechanics level and allows simulations at the microsecond timescale. Application of this approach the second hydride transfer transition state of HMG-CoA reductase from <i>Pseudomonas mevalonii </i>(<i>Pm</i>HMGR) identified three remote residues, R396 E399 and L407, (15-27 Å away from the active site) that have a remote dynamic effect on enzyme activity. The predictions were subsequently validated experimentally via site-directed mutagenesis. These results show that microsecond timescale MD simulations of transition states are possible and can predict rather than just rationalize remote allosteric residues.</p>

scholarly journals Microsecond Timescale Simulations at the Transition State of PmHMGR Predict Remote Allosteric Residues

2019 ◽  
Author(s):  
Taylor Quinn ◽  
Calvin N. Steussy ◽  
Brandon E. Haines ◽  
Jinping Lei ◽  
Wei Wang ◽  
...  
Keyword(s):  
Transition State ◽  
Molecular Mechanics ◽  
Conformational Changes ◽  
Enzymatic Catalysis ◽  
Dynamic Effect ◽  
Md Simulations ◽  
Site Directed Mutagenesis ◽  
Pseudomonas Mevalonii ◽  
Remote Residues ◽  
Coa Reductase

<p>Understanding the mechanisms of enzymatic catalysis requires a detailed understanding of the complex interplay of structure and dynamics of large systems that is a challenge for both experimental and computational approaches. QM/MM methods have been extensively used to study these reactions, but the difficulties arising from the hybrid treatment of the system are well documented. More importantly, the computational demands of QM/MM simulations mean that the dynamics of the reaction can only be considered on a timescale of nanoseconds even though the conformational changes needed to react the catalytically active state happen on a much slower timescale. Here we demonstrate an alternative approach that uses transition state force fields (TSFFs) derived by the quantum-guided molecular mechanics (Q2MM) method that provides a consistent treatment of the entire system at the classical molecular mechanics level and allows simulations at the microsecond timescale. Application of this approach the second hydride transfer transition state of HMG-CoA reductase from <i>Pseudomonas mevalonii </i>(<i>Pm</i>HMGR) identified three remote residues, R396 E399 and L407, (15-27 Å away from the active site) that have a remote dynamic effect on enzyme activity. The predictions were subsequently validated experimentally via site-directed mutagenesis. These results show that microsecond timescale MD simulations of transition states are possible and can predict rather than just rationalize remote allosteric residues.</p>

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