Improving the study of proton transfers between amino acid side chains in solution: choosing appropriate DFT functionals and avoiding hidden pitfalls

Silva, Pedro J.; Perez, Marta A. S.; Brás, Natércia F.; Fernandes, Pedro A.; Ramos, María J.

doi:10.1007/s00214-012-1179-x

Cited by 7 publications

(3 citation statements)

References 46 publications

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“…The prediction was that the H-bond with lysine would be neutral in low-polarity environment, whereas the bridge is ionic with arginine in any environment. In partial disagreement with the above results, Silva et al , [ 241 ] advocated the ionic character of any salt-bridge if an Asp side chain, as the acid partner is involved. These authors emphasized the need for considering more than three explicit water molecules and accounting for vibrational contributions to the total relative free energy even when a continuum solvent model is being applied.…”

Section: Conformational Equilibriamentioning

confidence: 89%

Competing Intramolecular vs. Intermolecular Hydrogen Bonds in Solution

Nagy

2014

IJMS

151

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A hydrogen bond for a local-minimum-energy structure can be identified according to the definition of the International Union of Pure and Applied Chemistry (IUPAC recommendation 2011) or by finding a special bond critical point on the density map of the structure in the framework of the atoms-in-molecules theory. Nonetheless, a given structural conformation may be simply favored by electrostatic interactions. The present review surveys the in-solution competition of the conformations with intramolecular vs. intermolecular hydrogen bonds for different types of small organic molecules. In their most stable gas-phase structure, an intramolecular hydrogen bond is possible. In a protic solution, the intramolecular hydrogen bond may disrupt in favor of two solute-solvent intermolecular hydrogen bonds. The balance of the increased internal energy and the stabilizing effect of the solute-solvent interactions regulates the new conformer composition in the liquid phase. The review additionally considers the solvent effects on the stability of simple dimeric systems as revealed from molecular dynamics simulations or on the basis of the calculated potential of mean force curves. Finally, studies of the solvent effects on the type of the intermolecular hydrogen bond (neutral or ionic) in acid-base complexes have been surveyed.

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Section: Conformational Equilibriamentioning

confidence: 89%

Competing Intramolecular vs. Intermolecular Hydrogen Bonds in Solution

Nagy

2014

IJMS

151

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“…Examples of QM/MM studies for which we have employed this general type of approaches include the enzymes HIV‐1 integrase, β‐hexosaminidase, β‐glycosidase, and isocitrate dehydrogenase, among others. Interestingly, we have found that the best density functionals can vary significantly from problem to problem, but common choices include MPWB1K, or M06 . In many cases, however, we have found that B3LYP still remains a safe choice, particularly when used in combination with large basis sets and with a dispersion correction .…”

Section: Types Of Qm/mm Schemesmentioning

confidence: 99%

Application of quantum mechanics/molecular mechanics methods in the study of enzymatic reaction mechanisms

Sousa

Ribeiro

Neves

et al. 2016

WIREs Comput Mol Sci

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162

118

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Quantum mechanics/molecular mechanics (QM/MM) methods offer a very appealing option for the computational study of enzymatic reaction mechanisms, by separating the problem into two parts that can be treated with different computational methods. Hence, in a QM/MM formalism, the part of the system in which catalysis actually occurs and that involves the active site, substrates and directly participating amino acid residues is treated at an adequate quantum mechanical level to describe the chemistry taking place. For the remaining of the enzyme, which does not participate directly in the reaction, but that typically involves a much larger number of atoms, molecular mechanics is employed, traditionally through the application of a biomolecular force field. When applied with care, QM/MM methods can be used with great advantage in comparing, at a structural and energetic level, different mechanistic proposals, discarding mechanistic alternatives and proposing new mechanistic pathways that are consistent with the available experimental data. With time, diverse flavors within the QM/MM methods have emerged, differing in a variety of technical and conceptual aspects. Hence present alternatives differ between additive and subtractive QM/MM schemes, the type of boundary schemes, and the way in which the electrostatic interactions between the two regions are accounted for. Also, single‐conformation QM/MM, multi‐PES approaches, and QM/MM Molecular Dynamics coexist today, each type with its own advantages and limitations. This review focuses on the application of QM/MM methods in the study of enzymatic reaction mechanisms, briefly presenting also the most important technical aspects involved in these calculations. Particular attention is dedicated to the application of the single‐conformation QM/MM, multi‐PES QM/MM studies, and QM/MM‐FEP methods and to the advantages and disadvantages of the different types of QM/MM. Recent breakthroughs are also introduced. A selection of hand‐picked examples is used to illustrate such features. WIREs Comput Mol Sci 2017, 7:e1281. doi: 10.1002/wcms.1281 This article is categorized under: Structure and Mechanism > Computational Biochemistry and Biophysics Structure and Mechanism > Reaction Mechanisms and Catalysis Electronic Structure Theory > Combined QM/MM Methods

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“…The latter paper includes a discussion related to the glycine zwitterion formation and the observed contradictions between experiment and theoretical calculations. A recent study [200] deals with the problem of the proton transfers between amino acid side chains in solution.…”

Section: Zwitterionic Amino Acidsmentioning

confidence: 99%

Theoretical Calculations on the Conformational/Tautomeric Equilibria for Small Molecules in Solution

Nagy

2014

Biochem & Pharmacol

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The prevailing conformation and/or tautomeric form of a species may affect the product in chemical reactions. Determination of the predominant ligand structure is also important in theoretical drug design, where the goal is finding the best fit between the structurally flexible ligand and the receptor. The present review surveys the computational problems encountered in structure determination of small organic molecules in solution. The discussed issues include the method of the geometry optimization, the needed level of theory and basis set, choice of the modeling parameters, and the determination of the relative standard chemical potentials for estimating the equilibrium constant in relation to the molar concentration of the participants through the chemical transformation.

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Improving the study of proton transfers between amino acid side chains in solution: choosing appropriate DFT functionals and avoiding hidden pitfalls

Cited by 7 publications

References 46 publications

Competing Intramolecular vs. Intermolecular Hydrogen Bonds in Solution

Competing Intramolecular vs. Intermolecular Hydrogen Bonds in Solution

Application of quantum mechanics/molecular mechanics methods in the study of enzymatic reaction mechanisms

Theoretical Calculations on the Conformational/Tautomeric Equilibria for Small Molecules in Solution

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