Biomolecular QM/MM Simulations: What Are Some of the “Burning Issues”?

Cui, Qiang; Pal, Tanmoy; Xie, Luke

doi:10.1021/acs.jpcb.0c09898

Cited by 103 publications

(100 citation statements)

References 187 publications

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“…Calculations of energy profiles of chemical reactions in proteins constitute an important part of studies on enzyme catalysis. The application of different versions of the quantum mechanics/molecular mechanics (QM/MM) method is a commonly accepted practice in this field [ 1 , 2 , 3 , 4 , 5 ]. In many cases, essential features of catalytic reaction mechanisms can be revealed by the results of QM/MM calculations of minimum energy profiles on the potential energy surface of a model system, for example, [ 6 , 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

Mechanism of Guanosine Triphosphate Hydrolysis by the Visual Proteins Arl3-RP2: Free Energy Reaction Profiles Computed with Ab Initio Type QM/MM Potentials

et al. 2021

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We report the results of calculations of the Gibbs energy profiles of the guanosine triphosphate (GTP) hydrolysis by the Arl3-RP2 protein complex using molecular dynamics (MD) simulations with ab initio type QM/MM potentials. The chemical reaction of GTP hydrolysis to guanosine diphosphate (GDP) and inorganic phosphate (Pi) is catalyzed by GTPases, the enzymes, which are responsible for signal transduction in live cells. A small GTPase Arl3, catalyzing the GTP → GDP reaction in complex with the activating protein RP2, constitute an essential part of the human vision cycle. To simulate the reaction mechanism, a model system is constructed by motifs of the crystal structure of the Arl3-RP2 complexed with a substrate analog. After selection of reaction coordinates, energy profiles for elementary steps along the reaction pathway GTP + H2O → GDP + Pi are computed using the umbrella sampling and umbrella integration procedures. QM/MM MD calculations are carried out, interfacing the molecular dynamics program NAMD and the quantum chemistry program TeraChem. Ab initio type QM(DFT)/MM potentials are computed with atom-centered basis sets 6-31G** and two hybrid functionals (PBE0-D3 and ωB97x-D3) of the density functional theory, describing a large QM subsystem. Results of these simulations of the reaction mechanism are compared to those obtained with QM/MM calculations on the potential energy surface using a similar description of the QM part. We find that both approaches, QM/MM and QM/MM MD, support the mechanism of GTP hydrolysis by GTPases, according to which the catalytic glutamine side chain (Gln71, in this system) actively participates in the reaction. Both approaches distinguish two parts of the reaction: the cleavage of the phosphorus-oxygen bond in GTP coupled with the formation of Pi, and the enzyme regeneration. Newly performed QM/MM MD simulations confirmed the profile predicted in the QM/MM minimum energy calculations, called here the pathway-I, and corrected its relief at the first elementary step from the enzyme–substrate complex. The QM/MM MD simulations also revealed another mechanism at the part of enzyme regeneration leading to pathway-II. Pathway-II is more consistent with the experimental kinetic data of the wild-type complex Arl3-RP2, whereas pathway-I explains the role of the mutation Glu138Gly in RP2 slowing down the hydrolysis rate.

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Section: Introductionmentioning

confidence: 99%

Mechanism of Guanosine Triphosphate Hydrolysis by the Visual Proteins Arl3-RP2: Free Energy Reaction Profiles Computed with Ab Initio Type QM/MM Potentials

et al. 2021

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“…136 Numerous molecular simulation packages, such as CHARMM, AMBER, NAMD, OpenMM, Gaussian, Q-Chem, Turbomole, Psi4, ORCA, and Gromacs, have QM/MM functionalities with built-in QM modules or interfaces. 137…”

Section: Computational Studiesmentioning

confidence: 99%

Metal Complexes as DNA Synthesis and/or Repair Inhibitors: Anticancer and Antimicrobial Agents

Ngoepe

Clayton

2021

Pharmaceutical Fronts

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Medicinal inorganic chemistry involving the utilization of metal-based compounds as therapeutics has become a field showing distinct promise. DNA and RNA are ideal drug targets for therapeutic intervention in the case of various diseases, such as cancer and microbial infection. Metals play a vital role in medicine, with at least 10 metals known to be essential for human life and a further 46 nonessential metals having been involved in drug therapies and diagnosis. These metal-based complexes interact with DNA in various ways, and are often delivered as prodrugs which undergo activation in vivo. Metal complexes cause DNA crosslinking, leading to the inhibition of DNA synthesis and repair. In this review, the various interactions of metal complexes with DNA nucleic acids, as well as the underlying mechanism of action, were highlighted. Furthermore, we also discussed various tools used to investigate the interaction between metal complexes and the DNA. The tools included in vitro techniques such as spectroscopy and electrophoresis, and in silico studies such as protein docking and density-functional theory that are highlighted for preclinical development.

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“…Using molecular dynamics (MD) and multilevel approaches like quantum mechanics/molecular mechanics (QM/MM) simulations help to balance the cost and accuracy in studying enzyme electronic structure along with suitable sampling. 44 Fluctuations, for example in electrostatic potential, are increasingly recognized as playing an important role in enzyme action that mandate efficient sampling to identify. [45][46][47][48][49] Moreover, it is essential to treat the active site and surrounding key residues with QM to quantify the bond rearrangement, polarization, and charge transfer.…”

Section: Introductionmentioning

confidence: 99%

Influence of the Greater Protein Environment on the Electrostatic Potential in Metalloenzyme Active Sites: the Case of Formate Dehydrogenase

Nazemi

Steeves

Kulik

2021

Preprint

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The Mo/W containing metalloenzyme formate dehydrogenase (FDH) is an efficient and selective natural catalyst which reversibly converts CO2 to formate under ambient conditions. A greater understanding of the role of the protein environment in determining the local properties of the FDH active site would enable rational bioinspired catalyst design. In this study, we investigate the impact of the greater protein environment on the electrostatic potential (ESP) of the active site. To model the enzyme environment, we used a combination of long-timescale classical molecular dynamics (MD) and multiscale quantum-mechanical/molecular-mechanical (QM/MM) simulations. We leverage the charge shift analysis method to systematically construct QM regions and analyze the electronic environment of the active site by evaluating the degree of charge transfer between the core active site and the protein environment. The contribution of the terminal chalcogen ligand to the ESP of the metal center is substantial and dependent on the chalcogen identity, with ESPs less negative and similar for Se and S terminal chalcogens than for O regardless of whether the Mo6+ or W6+ metal center is present. Our evaluation reveals that the orientation of the sidechains and ligand conformations will alter the relative trends in the ESP observed for a given metal center or terminal chalcogen, highlighting the importance of sampling dynamic fluctuations in the protein. Overall, our observations suggest that the terminal chalcogen ligand identity plays an important role in the enzymatic activity of FDH.

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Biomolecular QM/MM Simulations: What Are Some of the “Burning Issues”?

Cited by 103 publications

References 187 publications

Mechanism of Guanosine Triphosphate Hydrolysis by the Visual Proteins Arl3-RP2: Free Energy Reaction Profiles Computed with Ab Initio Type QM/MM Potentials

Mechanism of Guanosine Triphosphate Hydrolysis by the Visual Proteins Arl3-RP2: Free Energy Reaction Profiles Computed with Ab Initio Type QM/MM Potentials

Metal Complexes as DNA Synthesis and/or Repair Inhibitors: Anticancer and Antimicrobial Agents

Influence of the Greater Protein Environment on the Electrostatic Potential in Metalloenzyme Active Sites: the Case of Formate Dehydrogenase

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