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A combination of the gas-phase laser spectroscopy and quantum chemistry approaches is employed to explain the properties of a two-residue model peptide. The application of the technique in explaining the different dispersive interactions is also explained.

Until now, atomistic simulations of DNA and RNA and their complexes have been executed using well calibrated but conceptually simple pair-additive empirical potentials (force fields). Although such simulations provided many valuable results, it is well established that simple force fields also introduce errors into the description, underlying the need for development of alternative anisotropic, polarizable molecular mechanics (APMM) potentials. One of the most abundant forces in all kinds of nucleic acids topologies is base stacking. Intra- and interstrand stacking is assumed to be the most essential factor affecting local conformational variations of B-DNA. However, stacking also contributes to formation of all kinds of noncanonical nucleic acids structures, such as quadruplexes or folded RNAs. The present study focuses on 14 stacked cytosine (Cyt) dimers and the doubly H-bonded dimer. We evaluate the extent to which an APMM procedure, SIBFA, could account quantitatively for the results of high-level quantum chemistry (QC) on the total interaction energies, and the individual energy contributions and their nonisotropic behaviors. Good agreements are found at both uncorrelated HF and correlated DFT and CCSD(T) levels. Resorting in SIBFA to distributed QC multipoles and to an explicit representation of the lone pairs is essential to respectively account for the anisotropies of the Coulomb and of the exchange-repulsion QC contributions.

Using polarizable molecular mechanics, a recent study [de Courcy et al. J. Am. Chem. Soc., 2010, 132, 3312] has compared the relative energy balances of five competing inhibitors of the FAK kinase. It showed that the inclusion of structural water molecules was indispensable for an ordering consistent with the experimental one. This approach is now extended to compare the binding affinities of four active site ligands to the Type I Zn-metalloenzyme phosphomannose isomerase (PMI) from Candida albicans. The first three ones are the PMI substrate β-D-mannopyranose 6-phosphate (β-M6P) and two isomers, α-D-mannopyranose 6-phosphate (α-M6P) and β-D-glucopyranose 6-phosphate (β-G6P). They have a dianionic 6-phosphate substituent and differ by the relative configuration of the two carbon atoms C1 and C2 of the pyranose ring. The fourth ligand, namely 6-deoxy-6-dicarboxymethyl-β-D-mannopyranose (β-6DCM), is a substrate analogue that has the β-M6P phosphate replaced by the nonhydrolyzable phosphate surrogate malonate. In the energy-minimized structures of all four complexes, one of the ligand hydroxyl groups binds Zn(II) through a water molecule, and the dianionic moiety binds simultaneously to Arg304 and Lys310 at the entrance of the cavity. Comparative energy-balances were performed in which solvation of the complexes and desolvation of PMI and of the ligands are computed using the Langlet-Claverie continuum reaction field procedure. They resulted into a more favorable balance in favor of β-M6P than α-M6P and β-G6P, consistent with the experimental results that show β-M6P to act as a PMI substrate, while α-M6P and β-G6P are inactive or at best weak inhibitors. However, these energy balances indicated the malonate ligand β-6DCM to have a much lesser favorable relative complexation energy than the substrate β-M6P, while it has an experimental 10-fold higher affinity than it on Type I PMI from Saccharomyces cerevisiae. The energy calculations were validated by comparison with parallel ab initio quantum chemistry on model binding sites extracted from the energy-minimized PMI-inhibitor complexes. We sought to improve the models upon including explicit water molecules solvating the dianionic moieties in their ionic bonds with the Arg304 and Lys310 side-chains. Energy-minimization resulted in the formation of three networks of structured waters. The first water of each network binds to one of the three accessible anionic oxygens. The networks extend to PMI residues (Asp17, Glu48, Asp300) remote from the ligand binding site. The final comparative energy balances also took into account ligand desolvation in a box of 64 waters. They now resulted into a large preference in favor of β-6DCM over β-M6P. The means to further augment the present model upon including entropy effects and sampling were discussed. Nevertheless a clear-cut conclusion emerging from this as well as our previous study on FAK kinase is that both polarization and charge-transfer contributions are critical elements of the energy balances.

Using polarizable molecular mechanics (PMM), we have compared the complexation energies of the focal adhesion kinase (FAK) kinase by five inhibitors in the pyrrolopyrimidine series. These inhibitors only differ by the substitution position of a carboxylate group on their benzene or pyridine rings, and/or the length of the connecting (CH2)(n) chain (n = 0-2) while their inhibitory properties vary from micromolar to nanomolar. Energy balances in which solvation/desolvation effects are computed by a continuum reaction field procedure failed to rank the inhibitors according to their inhibitory potencies. In marked contrast, including energy-minimizing in the protein-inhibitor binding site limited numbers of structural water molecules, namely five to seven, ranked these energy balances conforming to the experimental ordering. The polarization energy contribution was the most critical energy contribution that stabilized the best-bound inhibitor over the others. These results imply that (a) upon docking charged inhibitors into the active site of kinases such as FAK, the presence of a limited number of structured water molecules is critical to enable meaningful relative energy balances and (b) accounting for an explicit polarization contribution within DeltaE is indispensable.

Following a previous study by de Courcy et al. ((2009) Interdiscip. Sci. Comput. Life Sci. 1, 55-60), we demonstrate in this contribution, using quantum chemistry, that metal cations exhibit a specific topological signature in the electron localization of their density interacting with ligands according to its "soft" or "hard" character. Introducing the concept of metal cation subvalence, we show that a metal cation can split its outer-shell density (the so-called subvalent domains or basins) according to it capability to form a partly covalent bond involving charge transfer. Such behaviour is investigated by means of several quantum chemical interpretative methods encompasing the topological analysis of the Electron Localization Function (ELF) and Bader's Quantum Theory of Atoms in Molecules (QTAIM) and two energy decomposition analyses (EDA), namely the Restricted Variational Space (RVS) and Constrained Space Orbital Variations (CSOV) approaches. Further rationalization is performed by computing ELF and QTAIM local properties such as electrostatic distributed moments and local chemical descriptors such as condensed Fukui Functions and dual descriptors. These reactivity indexes are computed within the ELF topological analysis in addition to QTAIM offering access to non atomic reactivity local index, for example on lone pairs. We apply this "subvalence" concept to study the cation selectivity in enzymes involved in blood coagulation (GLA domains of three coagulation factors). We show that the calcium ions are clearly able to form partially covalent charge transfer networks between the subdomain of the metal ion and the carboxylate oxygen lone pairs whereas magnesium does not have such ability. Our analysis also explains the different role of two groups (high affinity and low affinity cation binding sites) present in GLA domains. If the presence of Ca(II) is mandatory in the central "high affinity" region to conserve a proper folding and a charge transfer network, external sites are better stabilised by Mg(II), rather than Ca(II), in agreement with experiment. The central role of discrete water molecules is also discussed in order to understand the stabilities of the observed X-rays structures of the Gla domain. Indeed, the presence of explicit water molecules generating indirect cation-protein interactions through water networks is shown to be able to reverse the observed electronic selectivity occuring when cations directly interact with the Gla domain without the need of water.

We analyze the intermolecular interaction energies stabilizing the complex of ethanol in the binding site of alcohol dehydrogenase Zn-metalloenzyme (ADH). In this site Zn(II) is ligated by two cysteine and one imidazole residue and by the ethanol substrate. Ethanol is stacked over a phenylalanine residue. The system has been studied by means of SIBFA (Sum of Interactions Between Fragments Ab initio computed) polarizable molecular mechanics (PMM) supplemented by quantum chemical (QC) computations at various levels of theory. The nonadditivities of the QC interaction energies can be traced back by energy-decomposition analyses and are essentially due to polarization, charge-transfer, and electron correlation energies. These contributions can be reproduced by PMM computations. Interestingly, the polarization energy associated with the presence of the benzene ring in the ADH complex is canceled due to many-body/nonadditivity effects. Therefore this ring does not contribute to stabilization prior to including electron correlation/dispersion effects in the QC calculations or in the absence of the PMM dispersion energy contribution. When these effects are taken into account, the stabilization it contributes is in the 3-9 kcal/mol range, reflecting the need for an accurate reproduction of all components of the interaction energy by PMM.