Robust Predictive Power of the Electrostatic Term at Shortened Intermolecular Distances

At distances shorter than equilibrium, electrostatic interactions seem to be a more robust indicator of relative molecular dimer stability than more accurate electronic structure approaches. We arrive at this conclusion by investigating the nonparametric correlation between reference interaction energies at equilibrium geometries (coupled cluster with singles, doubles, and perturbative triples at the complete basis set limit, Δ<i>E</i>_CCSD(T)^CBS,ref) and its various approximate values obtained at a range of distances for a training set of 22 biologically relevant dimers. The reference and other costly methods start to fail to reproduce the equilibrium ranking of dimer stabilities when the intermolecular distance is shortened by more than 0.2 Å, but the full electrostatic component (includes penetration) maintains a high success rate. Such trends provide a new perspective for any applications where inaccurate structures are used out of necessity, such as the scoring of ligands docked to enzyme active sites

Alkaline Hydrolysis of Organophosphorus Pesticides: The Dependence of the Reaction Mechanism on the Incoming Group Conformation

The fundamental mechanism of organophosphate hydrolysis is the subject of a growing interest resulting from the need for safe disposal of phosphoroorganic pesticides. Herein, we present a detailed ab initio study of the gas-phase mechanisms of alkaline hydrolysis of P–O and P–S bonds in a number of organophosphorus pesticides, including paraoxon, methyl parathion, fenitrothion, demeton-S, acephate, phosalone, azinophos-ethyl, and malathion. Our main finding is that the incoming group conformation influences the mechanism of decomposition of organophosphate and organothiophosphate compounds. Depending on the orientation of the attacking nucleophile, hydrolysis reaction might follow either a multistep pathway characterized by the presence of a pentavalent intermediate or a one-step mechanism proceeding through a single transition state. Despite a widely accepted view of the phosphotriester P–O bonds being decomposed exclusively via a direct-displacement mechanism, the occurrence of alternative, qualitatively distinct reaction pathways was confirmed for alkaline hydrolysis of both P–O and P–S bonds. As the pesticides included in our quantum chemical analysis involve organophosphate, phosphorothioate, and phosphorodithioate compounds, the influence of oxygen to sulfur substitution on the structural and energetic characteristics of the hydrolysis pathway is also discussed

Robust Predictive Power of the Electrostatic Term at Shortened Intermolecular Distances

At distances shorter than equilibrium, electrostatic interactions seem to be a more robust indicator of relative molecular dimer stability than more accurate electronic structure approaches. We arrive at this conclusion by investigating the nonparametric correlation between reference interaction energies at equilibrium geometries (coupled cluster with singles, doubles, and perturbative triples at the complete basis set limit, Δ<i>E</i>_CCSD(T)^CBS,ref) and its various approximate values obtained at a range of distances for a training set of 22 biologically relevant dimers. The reference and other costly methods start to fail to reproduce the equilibrium ranking of dimer stabilities when the intermolecular distance is shortened by more than 0.2 Å, but the full electrostatic component (includes penetration) maintains a high success rate. Such trends provide a new perspective for any applications where inaccurate structures are used out of necessity, such as the scoring of ligands docked to enzyme active sites

Files from: Physical nature of ethidium and proflavine interactions with nucleic acid bases in the intercalation plane

<p>Atomic coordinates for the four molecular systems studied in <a href="http://dx.doi.org/10.1021/jp056836b">Physical nature of ethidium and proflavine interactions with nucleic acid bases in the intercalation plane, <em>J. Phys. Chem. B</em>,<em> </em><strong>2006</strong>, 110 (19), pp 9720–9727</a>.</p

Physical Nature of Fatty Acid Amide Hydrolase Interactions with Its Inhibitors: Testing a Simple Nonempirical Scoring Model

Fatty acid amide hydrolase (FAAH) is an enzyme responsible for the deactivating hydrolysis of fatty acid ethanolamide neuromodulators. FAAH inhibitors have gained considerable interest due to their possible application in the treatment of anxiety, inflammation, and pain. In the context of inhibitor design, the availability of reliable computational tools for predicting binding affinity is still a challenging task, and it is now well understood that empirical scoring functions have several limitations that in principle could be overcome by quantum mechanics. Herein, systematic ab initio analyses of FAAH interactions with a series of inhibitors belonging to the class of the <i>N</i>-alkylcarbamic acid aryl esters have been performed. In contrast to our earlier studies of other classes of enzyme–inhibitor complexes, reasonable correlation with experimental results required us to consider correlation effects along with electrostatic term. Therefore, the simplest comprehensive nonempirical model allowing for qualitative predictions of binding affinities for FAAH ligands consists of electrostatic multipole and second-order dispersion terms. Such a model has been validated against the relative stabilities of the benchmark S66 set of biomolecular complexes. As it does not involve parameters fitted to experimentally derived data, this model offers a unique opportunity for generally applicable inhibitor design and virtual screening

Files from: The Ethidium-UA/AU Intercalation Site: Effect of Model Fragmentation and Backbone Charge State

<p>Atomic coordinates for the molecular systems studied in <a href="http://dx.doi.org/10.1021/ct200121f">The ethidium-UA/AU intercalation site: effect of model fragmentation and backbone charge state, <em>J. Chem. Theory Comp.</em>, <strong>2011</strong>, 7, pp 2600-2609</a>.</p

Nonempirical Energetic Analysis of Reactivity and Covalent Inhibition of Fatty Acid Amide Hydrolase

Fatty acid amide hydrolase (FAAH) is a member of the amidase signature family and is responsible for the hydrolytic deactivation of fatty acid amide neuromodulators, such as anandamide. FAAH carries an unusual catalytic triad consisting of Lys-Ser-Ser, which uniquely enables the enzyme to cleave amides and esters at similar rates. The acylation of 9<i>Z</i>-octadecenamide (oleamide, a FAAH reference substrate) has been widely investigated by computational methods, and those have shown that conformational fluctuations of the active site affect the reaction barrier. Empirical descriptors have been devised to provide a possible mechanistic explanation for such conformational effects, but a first-principles understanding is still missing. A comparison of FAAH acylation with a reference reaction in water suggests that transition-state stabilization is crucial for catalysis because the activation energy barrier falls by 6 kcal/mol in the presence of the active site. With this in mind, we have analyzed the enzymatic reaction using the differential transition-state stabilization (DTSS) approach to determine key active-site residues for lowering the barrier. We examined several QM/MM structures at the MP2 level of theory and analyzed catalytic effects with a variation–perturbation partitioning of the interaction energy into electrostatic multipole and penetration, exchange, delocalization, and correlation terms. Three residues – Thr236, Ser218, and one water molecule – appear to be essential for the stabilization of the transition state, a conclusion that is also reflected by catalytic fields and agrees with site-directed mutagenesis data. An analogous analysis for URB524, URB618, and URB694 (three potent representatives of covalent, carbamate-based FAAH inhibitors) confirms the importance of the residues involved in oleamide acylation, providing insight for future inhibitor design