Unraveling non-covalent interactions within flexible biomolecules: from electron density topology to gas phase spectroscopy.

The NCI (Non-Covalent Interactions) method, a recently-developed theoretical strategy to visualize weak non-covalent interactions from the topological analysis of the electron density and of its reduced gradient, is applied in the present paper to document intra- and inter-molecular interactions in flexible molecules and systems of biological interest in combination with IR spectroscopy. We first describe the conditions of application of the NCI method to the specific case of intramolecular interactions. Then we apply it to a series of stable conformations of isolated molecules as an interpretative technique to decipher the different physical interactions at play in these systems. Examples are chosen among neutral molecular systems exhibiting a large diversity of interactions, for which an extensive spectroscopic characterization under gas-phase isolation conditions has been obtained using state-of-the-art conformer-specific experimental techniques. The interactions presently documented range from weak intra-molecular H-bonds in simple amino-alcohols, to more complex patterns, with interactions of various strengths in model peptides, as well as in chiral bimolecular systems, where invaluable hints for the understanding of chiral recognition are revealed. We also provide a detailed technical appendix, which discusses the choices of cut-offs as well as the applicability of the NCI analysis to specific constrained systems, where local effects require attention. Finally, the NCI technique provides IR spectroscopists with an elegant visualization of the interactions that potentially impact their vibrational probes, namely the OH and NH stretching motions. This contribution illustrates the power and the conditions of use of the NCI technique, with the aim of providing an easy tool for all chemists, experimentalists and theoreticians, for the visualization and characterization of the interactions shaping complex molecular systems.

Gas-phase folding of a two-residue model peptide chain: on the importance of an interplay between experiment and theory.

In order to assess the ability of theory to describe properly the dispersive interactions that are ubiquitous in peptide and protein systems, an isolated short peptide chain has been studied using both gas-phase laser spectroscopy and quantum chemistry. The experimentally observed coexistence of an extended form and a folded form in the supersonic expansion was found to result from comparable Gibbs free energies for the two species under the high-temperature conditions (< or = 320 K) resulting from the laser desorption technique used to vaporize the molecules. These data have been compared to results obtained using a series of quantum chemistry methods, including DFT, DFT-D, and post-Hartree-Fock methods, which give rise to a wide range of relative stabilities predicted for these two forms. The experimental observation was best reproduced by an empirically dispersion-corrected functional (B97-D) and a hybrid functional with a significant Hartree-Fock exchange term (M06-2X). In contrast, the popular post-Hartree-Fock method MP2, which is often used for benchmarking these systems, had to be discarded because of a very large basis-set superposition error. The applicability of the atomic counterpoise correction (ACP) is also discussed. This work also introduces the mandatory theoretical examination of experimental abundances. DeltaH(0 K) predictions are clearly not sufficient for discussion of folding, as the conformation inversion temperature is crucial to the conformation determination and requires taking into account thermodynamical corrections (DeltaG) in order to computationally isolate the most stable conformation.

Understanding selectivity of hard and soft metal cations within biological systems using the subvalence concept. I. Application to blood coagulation: direct cation-protein electronic effects vs. indirect interactions through water networks.

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.

Importance of lone pair interactions/redistribution in hard and soft ligands within the active site of alcohol dehydrogenase Zn-metalloenzyme: Insights from electron localization function.

As a continuation of our previous work (de Courcy et al., 2008. J. Chem. Theo. Comput. 4 1659), lone pair-cation interactions were quantum-mechanically studied within the active site of the alcohol dehydrogenase Zn(II)-metalloenzyme by means of the topological analysis of the Electron Localization Function (ELF) and the Reduced Variational Space (RVS) energy decomposition analysis. Ligands lone pairs in direct interaction with the metal were shown to control the physical nature of the interaction as it appears to be dominated by polarization when the number of interacting lone pairs increases. Furthermore, we observed a peculiar behaviour of the cysteinate S(-) lone pairs which can redistribute and merge, thereby reducing their number to accommodate the zinc cation which also exhibits a consequent plasticity of its density outer shells which can delocalize towards ligands. Such observations should allow a deeper understanding of the usual softness/hardness concept of ions and ligands.