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

2018 ◽  
Vol 20 (31) ◽  
pp. 20650-20660 ◽  
Author(s):  
Heather J. Kulik
Keyword(s):  
Free Energy ◽  
Charge Transfer ◽  
Long Range ◽  
Enzyme Catalysis ◽  
Active Sites ◽  
Large Scale ◽  
Enzyme Active Sites ◽  
Energy Simulations

Large-scale QM/MM free energy simulations reveal long-range fluctuations in charges on residues in enzyme active sites during dynamics.

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 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>

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.

scholarly journals Revealing quantum mechanical effects in enzyme catalysis with large-scale electronic structure simulation

2019 ◽  
Vol 4 (2) ◽  
pp. 298-315 ◽  
Author(s):  
Zhongyue Yang ◽  
Rimsha Mehmood ◽  
Mengyi Wang ◽  
Helena W. Qi ◽  
Adam H. Steeves ◽  
...  
Keyword(s):  
Electronic Structure ◽  
Enzyme Catalysis ◽  
Active Sites ◽  
Large Scale ◽  
Quantum Mechanical ◽  
Length Scales ◽  
Mechanical Simulation ◽  
Mechanical Effects ◽  
Structure Simulation ◽  
Quantum Mechanical Effects

Large scale quantum mechanical simulation systematically reveals length scales over which electronically driven interactions occur at enzyme active sites.

Large-Scale Assessment of Binding Free Energy Calculations in Active Drug Discovery Projects

2020 ◽  
Author(s):  
Christina Schindler ◽  
Hannah Baumann ◽  
Andreas Blum ◽  
Dietrich Böse ◽  
Hans-Peter Buchstaller ◽  
...  
Keyword(s):  
Free Energy ◽  
Drug Discovery ◽  
Large Scale ◽  
Active Drug ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Energy Calculation ◽  
Large Scale Assessment ◽  
New Public ◽  
Binding Free Energy Calculations

Here we present an evaluation of the binding affinity prediction accuracy of the free energy calculation method FEP+ on internal active drug discovery projects and on a large new public benchmark set.<br>

Prediction of Alkanolamine pKa Values by Combined Molecular Dynamics Free Energy Simulations and ab initio Calculations

2019 ◽  
Author(s):  
Javad Noroozi ◽  
William Smith
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Ab Initio Calculations ◽  
Gas Phase ◽  
Quantum Chemical ◽  
Phase Reaction ◽  
Pka Values ◽  
Gas Phase Reaction ◽  
Reaction Free Energy ◽  
Energy Simulations

We use molecular dynamics free energy simulations in conjunction with quantum chemical calculations of gas phase reaction free energy to predict alkanolamines pka values. <br>

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