Quantitative Assessment of Electrostatic Embedding in Density Functional Theory Calculations of Biomolecular Systems

Fattebert, Jean‐Luc; Law, Richard; Bennion, Brian J.; Lau, Edmond Y.; Schwegler, Eric; Lightstone, Felice C.

doi:10.1021/ct900209y

Cited by 7 publications

(11 citation statements)

References 36 publications

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“…The nonelectrostatic contributions to the total energy are added a posteriori as additional terms in the energy. This approach is know in literature to provide reliable results and is commonly used to treat problems in the fields of chemistry and biochemistry . In studies of the electronic structure, electrostatic embedding leads sometimes to artifacts.…”

Section: Resultsmentioning

confidence: 99%

Modeling Solvatochromic Shifts Using the Orbital-Free Embedding Potential at Statistically Mechanically Averaged Solvent Density

et al. 2010

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The correspondence between the exact embedding potential and the pair of the electron densities--that of the embedded molecule and that of its environment [Wesolowski and Warshel, J. Phys. Chem. 1993, 97, 8050]--is used to generate the average embedding potential and to subsequently calculate the solvatochromic shifts in a number of organic chromophores in solvents of various polarities. The averaged embedding potential is evaluated at a fictitious electron density of the solvent, which is obtained by means of "dressing up" with electrons the classical site distributions derived from the statistical-mechanical, 3D molecular theory of solvation (aka 3D-RISM method) [Kovalenko In Molecular Theory of Solvation; Hirata, Ed.; Understanding Chemical Reactivity; 2003, Vol 24], self-consistently coupled with the electronic structure of the solute. The proposed approach to modeling solvatochromic shifts can be situated between the implicit and explicit type of models for the solvent. Numerical examples are given for the lowest-lying n --> pi* and pi --> pi* excitations.

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Section: Resultsmentioning

confidence: 99%

Modeling Solvatochromic Shifts Using the Orbital-Free Embedding Potential at Statistically Mechanically Averaged Solvent Density

et al. 2010

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“…The resulting Coulomb potential was used as the external potential for the QM calculation. To prepare the QM system, we terminated the bonds cut in the process of partitioning the atomistic simulation into a primary and secondary subsystem as described previously [ 58 ]. Water molecules were either fully included in the QM region or not at all.…”

Section: Methodsmentioning

confidence: 99%

A Wrench in the Works of Human Acetylcholinesterase: Soman Induced Conformational Changes Revealed by Molecular Dynamics Simulations

et al. 2015

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Irreversible inactivation of human acetylcholinesterase (hAChE) by organophosphorous pesticides (OPs) and chemical weapon agents (CWA) has severe morbidity and mortality consequences. We present data from quantum mechanics/molecular mechanics (QM/MM) and 80 classical molecular dynamics (MD) simulations of the apo and soman-adducted forms of hAChE to investigate the effects on the dynamics and protein structure when the catalytic Serine 203 is phosphonylated. We find that the soman phosphonylation of the active site Ser203 follows a water assisted addition-elimination mechanism with the elimination of the fluoride ion being the highest energy barrier at 6.5 kcal/mole. We observe soman-dependent changes in backbone and sidechain motions compared to the apo form of the protein. These alterations restrict the soman-adducted hAChE to a structural state that is primed for the soman adduct to be cleaved and removed from the active site. The altered motions and resulting structures provide alternative pathways into and out of the hAChE active site. In the soman-adducted protein both side and back door pathways are viable for soman adduct access. Correlation analysis of the apo and soman adducted MD trajectories shows that the correlation of gorge entrance and back door motion is disrupted when hAChE is adducted. This supports the hypothesis that substrate and product can use two different pathways as entry and exit sites in the apo form of the protein. These alternative pathways have important implications for the rational design of medical countermeasures.

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“…11,12,14-18 Also, geometry parameters of the stationary structures are very similar (Tables S2-S8 of ESI †). Since differences in the calculated ΔE ‡ cat for all the systems are in the range of 3 kcal mol −1 (M06-2X) and 7 kcal mol −1 (B3LYP), and since the accuracy for kinetics parameters of the methods used is in the range of ±3-7 kcal mol −1 , [40][41][42][43] a detailed comparative analysis of the reaction profiles was not possible to perform. However, the results clearly indicate that all studied ions could catalyze, albeit with different impact, the transfer of the sugar moiety in Kre2p reaction under in vivo conditions.…”

Section: Qm/mm and Kie Calculationsmentioning

confidence: 99%

A theoretical study on the catalytic mechanism of the retaining α-1,2-mannosyltransferase Kre2p/Mnt1p: the impact of different metal ions on catalysis

2014

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Glycosyltransferases are sugar-processing enzymes that require a specific metal ion cofactor for catalysis. In the presence of other ions the catalysis is often impaired. Here, for the first time, the enzymatic catalysis in the presence of various metal ions was modeled for a glycosyltransferase using a large enzymatic model. The catalytic mechanism of α-1,2-mannosyltransferase Kre2p/Mnt1p in the presence of Mn(2+) and other ions (Mg(2+), Zn(2+) and Ca(2+)) was modeled at the two hybrid DFT-QM/MM (M06-2X/OPLS2005 and B3LYP/OPLS2005) levels. Kinetic and structural parameters of transition states and intermediates, as well as kinetic isotope effects, were predicted and compared with available experimental and theoretical data. The catalysis in the presence of the metal ions is predicted as a stepwise SNi-like nucleophilic substitution reaction (DNint*AN(‡)DhAxh) via oxocarbenium ion intermediates. In the rate-determining step the leaving phosphate group of the donor substrate plays a role of the base catalyst. The predicted increased enzymatic reactivity (kcat: Zn(2+) ≈ Mg(2+) < Mn(2+) < Ca(2+)) correlated with the metal ion ability to polarize the Kre2p environment (Mg(2+) > Zn(2+) > Mn(2+) > Ca(2+)). The formation of the retained anomeric configuration in the product is controlled by a strict geometry of the active site of Kre2p. The 6-OH group of the attacking acceptor substrate may assist in protection of the anomeric carbon against unwanted hydrolysis by a through-space interaction with the electron deficient C1[double bond, length as m-dash]O5(+) moiety of the oxocarbenium-ion-like transition state.

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Quantitative Assessment of Electrostatic Embedding in Density Functional Theory Calculations of Biomolecular Systems

Cited by 7 publications

References 36 publications

Modeling Solvatochromic Shifts Using the Orbital-Free Embedding Potential at Statistically Mechanically Averaged Solvent Density

Modeling Solvatochromic Shifts Using the Orbital-Free Embedding Potential at Statistically Mechanically Averaged Solvent Density

A Wrench in the Works of Human Acetylcholinesterase: Soman Induced Conformational Changes Revealed by Molecular Dynamics Simulations

A theoretical study on the catalytic mechanism of the retaining α-1,2-mannosyltransferase Kre2p/Mnt1p: the impact of different metal ions on catalysis

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