Computational methods for the study of enzymic reaction mechanisms III: A perturbation plus QM/MM approach for calculating relative free energies of protonation

2005 ◽  
Vol 26 (6) ◽  
pp. 561-568 ◽  
Author(s):  
Peter L. Cummins ◽  
Jill E. Gready
Keyword(s):  
Computational Methods ◽  
Reaction Mechanisms ◽  
Free Energies ◽  
Enzymic Reaction

Fluorinated substrate analogs as stereochemical probes of enzymic reaction mechanisms

Biochemistry ◽  
1978 ◽  
Vol 17 (25) ◽  
pp. 5567-5575 ◽  
Author(s):  
Jorge A. Goldstein ◽  
Yak-Fa Cheung ◽  
Michael A. Marletta ◽  
Christopher Walsh
Keyword(s):  
Reaction Mechanisms ◽  
Substrate Analogs ◽  
Enzymic Reaction

scholarly journals The reaction mechanism of the azide–alkyne Huisgen cycloaddition

2019 ◽  
Vol 21 (35) ◽  
pp. 19281-19287 ◽  
Author(s):  
Martina Danese ◽  
Marta Bon ◽  
GiovanniMaria Piccini ◽  
Daniele Passerone
Keyword(s):  
Reaction Mechanism ◽  
Computational Methods ◽  
Free Energies

By means of computational methods to sample reaction free energies, this paper provides novel insights into the Huisgen cycloaddition mechanism.

Lithium Cuprate Coupling Reactions: Evaluation of Computational Methods for Determination of the Reaction Mechanisms

2010 ◽  
Vol 114 (14) ◽  
pp. 5005-5015 ◽  
Author(s):  
Lawrence M. Pratt ◽  
Stewart Voit ◽  
Binh Khanh Mai ◽  
BichLien H. Nguyen
Keyword(s):  
Computational Methods ◽  
Reaction Mechanisms ◽  
Coupling Reactions

scholarly journals Evaluating the use of absolute binding free energy in the fragment optimization process.

2022 ◽  
Author(s):  
Irfan Alibay ◽  
Aniket Mangakar ◽  
Daniel Seeliger ◽  
Philip Biggin
Keyword(s):  
Free Energy ◽  
Computational Methods ◽  
Binding Free Energy ◽  
Optimization Process ◽  
Energy Estimates ◽  
Free Energies ◽  
Chemical Modifications ◽  
The Right ◽  
Absolute Binding Free Energy ◽  
Binding Free Energies

Key to the fragment optimization process is the need to accurately capture the changes in affinity that are associated with a given set of chemical modifications. Due to the weakly binding nature of fragments, this has proven to be a challenging task, despite recent advancements in leveraging experimental and computational methods. In this work, we evaluate the use of Absolute Binding Free Energy (ABFE) calculations in guiding fragment optimization decisions, retrospectively calculating binding free energies for 59 ligands across 4 fragment elaboration campaigns. We first demonstrate that ABFEs can be used to accurately rank fragment-sized binders with an overall Spearman’s r of 0.89 and a Kendall τ of 0.67, although often deviating from experiment in absolute free energy values with an RMSE of 2.75 kcal/mol. We then also show that in several cases, retrospective fragment optimization decisions can be supported by the ABFE calculations. Cases that were not supported were often limited by large uncertainties in the free energy estimates, however generally the right direction in ΔΔG is still observed. Comparing against cheaper endpoint methods, namely Nwat-MM/GBSA, we find that ABFEs offer better outcomes in ranking binders, improving correlation metrics, although a similar confidence in retrospective synthetic decisions is achieved. Our results indicate that ABFE calculations are currently at the level of accuracy that can be usefully employed to gauge which fragment elaborations are likely to offer the best gains in affinity.

A SIMPLIFIED APPROACH TO THE USE OF DETERMINANTS IN THE CALCULATION OF THE RATE EQUATION FOR A COMPLEX ENZYME SYSTEM

1967 ◽  
Vol 45 (12) ◽  
pp. 2015-2039 ◽  
Author(s):  
R. O. Hurst
Keyword(s):  
Reaction Mechanism ◽  
Rate Equation ◽  
Rate Constants ◽  
Reaction Mechanisms ◽  
Enzyme System ◽  
Inhibition Mechanism ◽  
Simplified Approach ◽  
Enzymic Reaction ◽  
Dead End ◽  
Search For Information

A standardized method of treating the analysis of enzymic reaction mechanisms by means of determinant expressions is given. The fully expanded polynomial expressions for systems of order three, four, and five are presented and their use described. Application of the method to the analysis of the effect of dead-end inhibitors on enzymic reactions is discussed and the inhibitor constants are evaluated in terms of the rate constants involved in the inhibition mechanism. Examples are given to demonstrate the contribution that inhibitor studies may make in the search for information concerning the nature of the enzymic reaction mechanism, in the calculation of the rate constants, and in the estimation of the proportion of the enzyme distributed between the different enzyme forms involved in the reaction.

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