Finite-temperature effects in enzymatic reactions — Insights from QM/MM free-energy simulations

2009 ◽  
Vol 87 (10) ◽  
pp. 1322-1337 ◽  
Author(s):  
Hans Martin Senn ◽  
Johannes Kästner ◽  
Jürgen Breidung ◽  
Walter Thiel
Keyword(s):  
Free Energy ◽  
Finite Temperature ◽  
Temperature Effects ◽  
Density Functional ◽  
Umbrella Sampling ◽  
Chorismate Mutase ◽  
Enzymatic Reactions ◽  
Energy Data ◽  
Energy Simulations ◽  
Entropic Contribution

We report potential-energy and free-energy data for three enzymatic reactions: carbon–halogen bond formation in fluorinase, hydrogen abstraction from camphor in cytochrome P450cam, and chorismate-to-prephenate Claisen rearrangement in chorismate mutase. The results were obtained by combined quantum mechanics/molecular mechanics (QM/MM) optimizations and two types of QM/MM free-energy simulations (free-energy perturbation and umbrella sampling) using semi-empirical or density-functional QM methods. Based on these results and our previously published free-energy data on electrophilic substitution in para-hydroxybenzoate hydroxylase, we discuss the importance of finite-temperature effects in the chemical step of enzyme reactions. We find that the entropic contribution to the activation barrier is generally rather small, usually of the order of 5 kJ mol–1 or less, consistent with the notion that enzymes bind and pre-organize the reactants in the active site. A somewhat larger entropic contribution is encountered in the case of chorismate mutase where the pericyclic transition state is intrinsically more rigid than the chorismate reactant (also in the enzyme). The present results suggest that barriers from QM/MM geometry optimization may often be close to free-energy barriers for the chemical step in enzymatic reactions.

Displacement of carbonates in Ca2UO2(CO3)3 by amidoxime-based ligands from free-energy simulations

2018 ◽  
Vol 47 (5) ◽  
pp. 1604-1613 ◽  
Author(s):  
Bo Li ◽  
Chad Priest ◽  
De-en Jiang
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Umbrella Sampling ◽  
Nacl Solution ◽  
Classical Molecular Dynamics ◽  
Energy Profiles ◽  
Energy Simulations ◽  
Dynamics Simulations ◽  
Free Energy Profiles

Classical molecular dynamics simulations coupled with umbrella sampling reveal the atomistic processes and free-energy profiles of the displacement of carbonate groups in the Ca2UO2(CO3)3 complex by amidoxime-based ligands in a 0.5 M NaCl solution.

scholarly journals Reconciling NMR Structures of the HIV-1 Nucleocapsid Protein (NCp7) using Extensive Polarizable Force Field Free-Energy Simulations

2019 ◽  
Author(s):  
Léa El Khoury ◽  
Frédéric Célerse ◽  
Louis Lagardere ◽  
Luc-Henri Jolly ◽  
Étienne Derat ◽  
...  
Keyword(s):  
Free Energy ◽  
Force Field ◽  
Water Solution ◽  
Energy Difference ◽  
Umbrella Sampling ◽  
Energy Stability ◽  
Functional Protein ◽  
Relative Free Energy ◽  
Energy Simulations ◽  
Experimental Findings

The Human Immunodeficiency Virus Type 1 nucleocapsid 7 (NCp7) is a multi-functional protein formed by N-terminal and C-terminal domains surrounding two Zn-fingers, linked by a stretch of basic residues, which play a key role in the viral replication. We report the first NCp7 polarizable molecular dynamics (MD) study using the AMOEBA force field complemented by non-polarizable CHARMM simulations. Specifically, we compared the relative free-energy stability of two extreme conformations: a compact one having two aromatic residues from each finger, partially stacked, denoted A; and an unfolded one, with the two residues apart, denoted B. Each of these conformations had been previously experimentally advocated to prevail in solution. We compared their theoretical relative free-energy stability using accelerated MD sampling techniques (Steered MD and Umbrella Sampling) and showed that there was a low free energy difference between them. As A and B do not differ in stability by more than 1-1.5 kcal/mol, they should thus coexist in water solution reconciling earlier NMR experimental findings.

scholarly journals Large-scale QM/MM free energy simulations of enzyme catalysis reveal the influence of charge transfer

2018 ◽  
Author(s):  
Heather Kulik
Keyword(s):  
Free Energy ◽  
Electronic Structure ◽  
Charge Transfer ◽  
Ab Initio ◽  
Density Functional ◽  
Large Scale ◽  
Active Site Residues ◽  
Functional Theory ◽  
Energy Simulations ◽  
Electrostatic Embedding

Hybrid quantum mechanical-molecular mechanical (QM/MM) simulations provide key insights into enzyme structure–function relationships. Numerous studies have demonstrated that large QM regions are needed to systematically converge ground state, zero temperature properties with electrostatic embedding QM/MM. However, it is not well known if <i>ab initio </i>QM/MM free energy simulations have this same dependence, in part due to the hundreds of thousands of energy evaluations required for free energy estimations that in turn limit QM region size. Here, we leverage recent advances in electronic structure efficiency and accuracy to carry out range-separated hybrid density functional theory free energy simulations in a representative methyltransferase. By studying 200 ps of <i>ab initio </i>QM/MM dynamics for each of five QM regions from minimal (64 atoms) to one-sixth of the protein (544 atoms), we identify critical differences between large and small QM region QM/MM in charge transfer between substrates and active site residues as well as in geometric structure and dynamics that coincide with differences in predicted free energy barriers. Distinct geometric and electronic structure features in the largest QM region indicate that important aspects of enzymatic rate enhancement in methyltransferases are identified with large-scale electronic structure.<br>

scholarly journals Machine Learning Assisted Free Energy Simulation of Solution–Phase and Enzyme Reactions

2021 ◽  
Author(s):  
Xiaoliang Pan ◽  
junjie yang ◽  
Richard Van ◽  
Evgeny Epifanovsky ◽  
Junming Ho ◽  
...  
Keyword(s):  
Machine Learning ◽  
Free Energy ◽  
Reaction Pathway ◽  
Molecular System ◽  
Computational Cost ◽  
Energy Simulation ◽  
Solution Phase ◽  
Chorismate Mutase ◽  
Enzymatic Reactions ◽  
Enzyme Reactions

Despite recent advances in the development of machine learning potentials (MLPs) for biomolecular simulations, there has been limited effort in developing stable and accurate MLPs for enzymatic reactions. Here, we report a protocol for performing machine learning assisted free energy simulation of solution-phase and enzyme reactions at an ab initio quantum mechanical and molecular mechanical (ai-QM/MM) level of accuracy. Within our protocol, the MLP is built to reproduce the ai-QM/MM energy as well as forces on both QM (reactive) and MM (solvent/enzyme) atoms. As an alternative strategy, a delta machine learning potential (DMLP) is trained to reproduce the differences between ai-QM/MM and semiempirical (se) QM/MM energy and forces. To account for the effect of the condensed–phase environment in both MLP and DMLP, the DeePMD representation of a molecular system is extended to incorporate external electrostatic potential and field on each QM atom. Using the Menshutkin and chorismate mutase reactions as examples, we show that the developed MLP and DMLP reproduce the ai-QM/MM energy and forces with an error on average less than 1.0 kcal/mol and 1.0 kcal/mol/Å for representative configurations along the reaction pathway. For both reactions, MLP/DMLP-based simulations yielded free energy profiles that differed by less than 1.0 kcal/mol from the reference ai-QM/MM results, but only at a fractional computational cost.<br>

scholarly journals Large-scale QM/MM free energy simulations of enzyme catalysis reveal the influence of charge transfer

2018 ◽  
Author(s):  
Heather Kulik
Keyword(s):  
Free Energy ◽  
Electronic Structure ◽  
Charge Transfer ◽  
Ab Initio ◽  
Density Functional ◽  
Large Scale ◽  
Active Site Residues ◽  
Functional Theory ◽  
Energy Simulations ◽  
Electrostatic Embedding

Hybrid quantum mechanical-molecular mechanical (QM/MM) simulations provide key insights into enzyme structure–function relationships. Numerous studies have demonstrated that large QM regions are needed to systematically converge ground state, zero temperature properties with electrostatic embedding QM/MM. However, it is not well known if <i>ab initio </i>QM/MM free energy simulations have this same dependence, in part due to the hundreds of thousands of energy evaluations required for free energy estimations that in turn limit QM region size. Here, we leverage recent advances in electronic structure efficiency and accuracy to carry out range-separated hybrid density functional theory free energy simulations in a representative methyltransferase. By studying 200 ps of <i>ab initio </i>QM/MM dynamics for each of five QM regions from minimal (64 atoms) to one-sixth of the protein (544 atoms), we identify critical differences between large and small QM region QM/MM in charge transfer between substrates and active site residues as well as in geometric structure and dynamics that coincide with differences in predicted free energy barriers. Distinct geometric and electronic structure features in the largest QM region indicate that important aspects of enzymatic rate enhancement in methyltransferases are identified with large-scale electronic structure.<br>

scholarly journals Combining free energy simulations and NMR chemical-shift perturbation to identify transient cation-π contacts in proteins

2019 ◽  
Author(s):  
André A. O. Reis ◽  
Raphael S. R. Sayegh ◽  
Sandro R. Marana ◽  
Guilherme M. Arantes
Keyword(s):  
Free Energy ◽  
Chemical Shift ◽  
Catalytic Domain ◽  
Chemical Shifts ◽  
Umbrella Sampling ◽  
Terminal Segment ◽  
Functional Roles ◽  
Energy Profiles ◽  
Energy Simulations ◽  
Dynamics Simulations

AbstractFlexible protein regions containing cationic and aromatic side-chains exposed to solvent may form transient cation-π interactions with structural and functional roles. To evaluate their stability and identify important intramolecular cation-π contacts, a combination of free energy profiles estimated from umbrella sampling with molecular dynamics simulations and chemical shift perturbations (CSP) obtained from NMR experiments is applied here to the complete catalytic domain of human phosphatase Cdc25B. This protein is a good model system for transient cation-π interactions as it contains only one Trp residue (W550) in the disordered C-terminal segment and a total of 17 Arg residues, many exposed to solvent. Eight putative Arg-Trp pairs were simulated here. Only R482 and R544 show bound profiles corresponding to important transient cation-π interactions, while the others have dissociative or almost flat profiles. These results are corroborated by CSP analysis of three Cdc25B point mutants (W550A, R482A and R544A) disrupting cation-π contacts. The proposed validation of statistically representative molecular simulations by NMR spectroscopy could be applied to identify transient contacts of proteins in general but carefully, as NMR chemical shifts are sensitive to changes in both molecular contacts and conformational distributions.

scholarly journals Molecular Simulations with in-deMon2k QM/MM, a Tutorial-Review

Molecules ◽  
2019 ◽  
Vol 24 (9) ◽  
pp. 1653 ◽  
Author(s):  
Aurélien de la Lande ◽  
Aurelio Alvarez-Ibarra ◽  
Karim Hasnaoui ◽  
Fabien Cailliez ◽  
Xiaojing Wu ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Ground State ◽  
Density Functional ◽  
Molecular Simulations ◽  
High Energy ◽  
Umbrella Sampling ◽  
Visible Absorption ◽  
Dynamics Simulations

deMon2k is a readily available program specialized in Density Functional Theory (DFT) simulations within the framework of Auxiliary DFT. This article is intended as a tutorial-review of the capabilities of the program for molecular simulations involving ground and excited electronic states. The program implements an additive QM/MM (quantum mechanics/molecular mechanics) module relying either on non-polarizable or polarizable force fields. QM/MM methodologies available in deMon2k include ground-state geometry optimizations, ground-state Born–Oppenheimer molecular dynamics simulations, Ehrenfest non-adiabatic molecular dynamics simulations, and attosecond electron dynamics. In addition several electric and magnetic properties can be computed with QM/MM. We review the framework implemented in the program, including the most recently implemented options (link atoms, implicit continuum for remote environments, metadynamics, etc.), together with six applicative examples. The applications involve (i) a reactivity study of a cyclic organic molecule in water; (ii) the establishment of free-energy profiles for nucleophilic-substitution reactions by the umbrella sampling method; (iii) the construction of two-dimensional free energy maps by metadynamics simulations; (iv) the simulation of UV-visible absorption spectra of a solvated chromophore molecule; (v) the simulation of a free energy profile for an electron transfer reaction within Marcus theory; and (vi) the simulation of fragmentation of a peptide after collision with a high-energy proton.

Charge Transfer Effects in Enzyme Catalysis Observed with Large-Scale QM/MM Free Energy Simulations

2018 ◽  
Author(s):  
Heather Kulik
Keyword(s):  
Free Energy ◽  
Electronic Structure ◽  
Charge Transfer ◽  
Ab Initio ◽  
Density Functional ◽  
Large Scale ◽  
Active Site Residues ◽  
Functional Theory ◽  
Energy Simulations ◽  
Electrostatic Embedding

Hybrid quantum mechanical-molecular mechanical (QM/MM) simulations provide key insights into enzyme structure–function relationships. Numerous studies have demonstrated that large QM regions are needed to systematically converge ground state, zero temperature properties with electrostatic embedding QM/MM. However, it is not well known if ab initio QM/MM free energy simulations have this same dependence, in part due to the hundreds of thousands of energy evaluations required for free energy estimations that in turn limit QM region size. Here, we leverage recent advances in electronic structure efficiency and accuracy to carry out range-separated hybrid density functional theory free energy simulations in a representative methyltransferase. By studying for 200 ps each of ab initio QM/MM dynamics in five QM regions from minimal (64 atoms) to one-sixth of the protein (544 atoms), we identify critical differences between large and small QM region QM/MM in charge transfer between substrates and active site residues as well as in geometric structure and dynamics that coincide with differences in predicted free energy barriers. Distinct geometric and electronic structure features in the largest QM region indicate that fundamental aspects of enzymatic rate enhancement are identified with large-scale electronic structure.

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