Hydration free energies in the FreeSolv database calculated with polarized iterative Hirshfeld charges

Computer simulations of biomolecular systems often use force fields, which are combinations of simple empirical atom-based functions to describe the molecular interactions. Even though polarizable force fields give a more detailed description of intermolecular interactions, nonpolarizable force fields, developed several decades ago, are often still preferred because of their reduced computation cost. Electrostatic interactions play a major role in biomolecular systems and are therein described by atomic point charges. In this work, we address the performance of different atomic charges to reproduce experimental hydration free energies in the FreeSolv database in combination with the GAFF force field. Atomic charges were calculated by two atoms-in-molecules approaches, Hirshfeld-I and Minimal Basis Iterative Stockholder (MBIS). To account for polarization effects, the charges were derived from the solute’s electron density computed with an implicit solvent model, and the energy required to polarize the solute was added to the free energy cycle. The calculated hydration free energies were analyzed with an error model, revealing systematic errors associated with specific functional groups or chemical elements. The best agreement with the experimental data is observed for the AM1-BCC and the MBIS atomic charge methods. The latter includes the solvent polarization and presents a root-mean-square error of 2.0 kcal mol–1 for the 613 organic molecules studied. The largest deviation was observed for phosphorus-containing molecules and the molecules with amide, ester and amine functional groups

An explicit approach to conceptual density functional theory descriptors of arbitrary order

We present explicit formulas for arbitrary-order derivatives of the energy, grand potential, electron density, and higher-order response functions with respect to the number of electrons, and the chemical potential for any smooth and differentiable model of the energy versus the number of electrons. The resulting expressions for global reactivity descriptors (hyperhardnesses and hypersoftnesses), local reactivity descriptors (hyperFukui functions and local hypersoftnesses), and nonlocal response functions are easy to evaluate computationally. Specifically, the explicit formulas for global/local/nonlocal hypersoftnesses of arbitrary order are derived using Bell polynomials. Explicit expressions for global and local hypersoftness indicators up to fifth order are presented. (C) 2016 Elsevier B.V. All rights reservedVanier-CGS fellowship Ghent University CONACYT FONDECYT 114031

Dynamik, Ionisation und Ladungstrennung in überhitzten metastabilem Wasser

Das Aufheizen eines Wasserstrahls im Vakuum mittels eines Infrarot(IR)-Lasers führt zu einer ultraschnellen Phasenexpansion.Dieser Prozess wurde mittels Molekular Dynamik Simulationen verfolgt und somit ein molekulares Bild zu zeitaufgelösten Photoelektronspektren geschaffen. Anhand der Simulationen konnte die Phasenexpansion in zwei Bereichen unterteilt werden: ein überkritischer und ein unterkritischer Bereich. Im unterkritischen Bereich findet der Prozess als Einzelmolekül Verdampfung an der flüssig-vakuum Grenzfläche statt. Bei überkritischen Temperaturen jedoch ist die Evolution der Phase schneller (~100ps). Änderungen in charakteristische Banden im Spektrum konnten anhand der Simulationen auf Veränderungen im Wasserstoffbrücken-Netzwerk zurückgeführt werden. Zudem konnten Aggregate in der Grösse von 5 bis 20 Molekülen in den Simulationen eine neue Bande im Spektrum identifizieren, die nach 200ps zu beobachten war. Des Weiteren konnte mittels QM-MM Berechnungen die Bandenverschiebung in den Spektren durch eine Destabilisierung des Grundzustands und des ionisierten Zustands auf Grund von Wasserstoffbrücken erklärt werden.Ein IR-Laser findet auch Verwendung bei der Isolation von Ionen oder geladenen Moleküle aus einem Wasser Filament zur massenspektrometrischer Analyse. MD-Simulationen von Modell Systemen, die das Wasser Filament und den Einfluss des IR-Lasers berücksichtigen, zeigten dass Schockwellen die Flüssigkeit in kleinere Volumina zerteilen. Der geringe Temperaturanstieg in den gebildeten Volumina erklären die Sanftheit der Methode, mit der sich labile Protein-Komplexe massenspektrometrisch charakterisieren lassen.Des weiteren wurde der Mechanismus der Ladungstrennung während der Dispersion untersucht. Die Wahrscheinlichkeit, ein geladenes Volumen nach der Dispersion zu erhalten, konnte in Abhängigkeit der Ionenkonzentration in drei Bereiche unterteilt werden. Für Konzentrationen kleiner als 0.001M kann die Ladungswahrscheinlichkeit mittels eines analytischen Ausdrucks unter der Annahme einer Poisson Verteilung für die Anzahl an Ionen berechnet werden. Bei höherer Ionenkonzentration muss die Korrelation zwischen den Ionen in Betracht gezogen werden, welche die Wahrscheinlichkeit einer Ladung reduziert. MD-Simulationen waren nötig um einen Ionenfluss während der Dispersion bei Konzentrationen grösser als 0.1M auszumachen. Dieser Ionenfluss nimmt bei höher geladenen Volumina zu und führt zu einer weiteren Reduzierung der Ladungswahrscheinlichkeit

SAMPL6 Octanol-Water Partition Coefficients from Alchemical Free Energy Calculations with MBIS Atomic Charges

In molecular modeling the description of the interactions between molecules forms the basis for a correct prediction of macroscopic observables. Here, we derive atomic charges from the implicitly polarized electron density of eleven molecules in the SAMPL6 challenge using the Hirshfeld-I and Minimal Basis Set Iterative Stockholder(MBIS) partitioning method. These atomic charges combined with other parameters in the GAFF force field and different water/octanol models were then used in alchemical free energy calculations to obtain hydration and solvation free energies, which after correction for the polarization cost, result in the blind prediction of the partition coefficient. From the tested partitioning methods and water models the S-MBIS atomic charges with the TIP3P water model presented the smallest deviation from the experiment. Conformational dependence of the free energies and the energetic cost associated with the polarization of the electron density are discussed

Conformational Sampling and Polarization of Asp26 in pKa Calculations of Thioredoxin

Thioredoxin is a protein that has been used as model system by various computational methods to predict the pKa of aspartate residue Asp26 which is 3.5 units higher than a solvent exposed one (e.g Asp20). Here, we use extensive atomistic molecular dynamics simulations of two different protonation states of Asp26 in combination with conformational analysis based on RMSD clustering and principle component analysis to identify representative conformations of the protein in solution. For each conformation the Gibbs free energy of proton transfer between Asp26 and Asp20, which is fully solvated in a loop region of the protein, is calculated with the Amber99sb force field in alchemical transformations. The varying polarization of the two residues in different molecular environments and protonation states is described by Hirshfeld-I (HI) atomic charges obtained from the averaged polarized electron density. Our results show that the Gibbs free energy of proton transfer is dependent on the protein conformation, the proper sampling of the neighbouring Lys57 residue orientations and on water molecules entering the hydrophobic cavity upon deprotonating Asp26. The inclusion of the polarization of both aspartate residues in the free energy cycle by the HI atomic charges improves the results from the nonpolarizable force field and reproduces the experimental pKa value of Asp26.<br /

Partition Coefficients of Methylated DNA Bases Obtained from Free Energy Calculations with Molecular Electron Density Derived Atomic Charges.

Partition coefficients serve in various areas as pharmacology and environmental sciences to predict the hydrophobicity of different substances. Recently, they have been also used to address the accuracy of force fields for various organic compounds and specifically the methylated DNA bases. In this study atomic charges were derived by different partitioning methods (Hirshfeld and Minimal Basis Iterative Stockholder) directly from the electron density obtained by electronic structure calculations in vac- uum, with an implicit solvation model or with explicit solvation taking the dynamics of the solute and the solvent into account. To test the ability of these charges to describe electrostatic interactions in force fields for condensed phases the original atomic charges of the AMBER99 force field were replaced with the new atomic charges and combined with different solvent models to obtain the hydration and chloroform solvation free energies by molecular dynamics simulations. Chloroform-water partition coefficients derived from the obtained free energies were compared to experimental and previously reported values obtained with the GAFF or the AMBER-99 force field. The results show that good agreement with experimental data is obtained when the polarization of the electron density by the solvent has been taken into account deriving the atomic charges of polar DNA bases and when the energy needed to polarize the electron den- sity of the solute has been considered in the transfer free energy. These results were further confirmed by hydration free energies of polar and aromatic amino acid side chain analogues. Comparison of the two partitioning methods Hirsheld-I and Minimal Basis Iterative Stockholder (MBIS) revealed some deficiencies in the Hirshfeld-I method related to nonexistent isolated anionic nitrogen pro-atoms used in the method. Hydration free energies and partitioning coefficients obtained with atomic charges from the MBIS partitioning method accounting for polarization by the implicit solvation model are in good agreement with the experimental values. </div

DFT Benchmark Study of the O--O Bond Dissociation Energy in Peroxides Validated with High-Level Ab-Initio Calculations

Peroxides play a central role in many chemical and biological pro- cesses such as the Fenton reaction. The relevance of these compounds lies in the low stability of the O–O bond which upon dissociation results in radical species able to initiate various chemical or biological processes. In this work, a set of 64 DFT functional-basis set combinations has been validated in terms of their capability to describe bond dissociation energies (BDE) for the O–O bond in a database of 14 ROOH peroxides for which experimental values ofBDE are available. Moreover, the electronic contributions to the BDE were obtained for four of the peroxides and the anion H2O2− at the CBS limit at CCSD(T) level with Dunning’s basis sets up to triple–ζ quality provid- ing a reference value for the hydrogen peroxide anion as a model. Almost all the functionals considered here yielded mean absolute deviations around 5.0 kcal mol−1. The smallest values were observed for the ωB97 family and the Minnesota M11 functional with a marked basis set dependence. Despite the mean deviation, order relations among BDE experimental values of peroxides were also considered. The ωB97 family was able to reproduce the relations correctly whereas other functionals presented a marked dependence on the chemical nature of the R group. Interestingly, M11 functional did not show a very good agreement with the established order despite its good performance in the mean error. The obtained results support the use of similar validation strategies for proper prediction of BDE or other molecular properties by DF Tmethods in subsequent related studies.</div

Molecular Environment Specific Atomic Charges Improve Binding Affinity Predictions of SAMPL5 Host-Guest Systems

Host-guest systems are widely used in benchmarks as model systems to improve computational methods for absolute binding free energy predictions. Recent advances in sampling algorithms for alchemical free energy calculations and the increase in computational power have made their binding affinity prediction primarily dependent on the quality of the force field. Here, we propose a new methodology to derive the atomic charges of host-guest systems based on QM/MM calculations and the MBIS partitioning of the polarized electron density. A newly developed interface between the OpenMM and ORCA software package provides D-MBIS charges that best represent the guest’s average electrostatic interactions in the hosts or the solvent. The simulation workflow also calculates the average energy required to polarize the guest in the bound and unbound state. Alchemical free energy calculations using the GAFF force field parameters with D-MBIS charges improve the binding affinity prediction of six guests bound to two octa-acid hosts compared to the AM1-BCC charge set after correction with the average energetic polarization cost. This correction results from the difference in the energetic polarization cost between the bound and unbound state and contributes significantly to the binding affinity of anionic guests

Atom Condensed Fukui Function for Condensed Phases and Biological Systems and Its Application to Enzymatic Fixation of Carbon Dioxide

Local reactivity descriptors such as atom condensed Fukui functions are promising computational tools to study chemical reactivity at specific sites within a molecule. Their applications have been mainly focused on isolated molecules in their most stable conformation without considering the effects of the surroundings. Here, we propose to combine QM/MM Born-Oppenheimer molecular dynamics simulations to obtain the microstates (configurations) of a molecular system using different representations of the molecular environment and calculate Boltzmann weighted atom condensed local reac- tivity descriptors based on conceptual DFT. Our approach takes the conformational fluctuations of the molecular system and the polarization of its electron density by the environment into account allowing us to analyze the effect of changes in the molecular environment on reactivity. In this contribution, we apply the method mentioned above to the catalytic fixation of carbon dioxide by crotonyl-CoA carboxylase/reductase and study if the enzyme alters the reactivity of its substrate compared to an aqueous solution. Our main result is that the protein en- vironment activates the substrate by the elimination of solute-solvent hydrogen bonds from aqueous solution in the two elementary steps of the reaction mechanism: the nucleophilic attack of a hydride anion from NADPH on the α, β unsaturated thioester and the electrophilic attack of carbon dioxide on the formed enolate species.</div