Robin Chaudret

Toward a deeper understanding of enzyme reactions using the coupled ELF/NCI analysis: Application to DNA repair enzymes

The combined Electron Localization Funtion (ELF)/ Noncovalent Interaction (NCI) topological analysis (Gillet et al. J. Chem. Theory Comput.2012, 8, 3993) has been extended to enzymatic reaction paths. We applied ELF/NCI to the reactions of DNA polymerase λ and the ε subunit of DNA polymerase III. ELF/NCI is shown to provide insights on the interactions during the evolution of enzymatic reactions including predicting the location of TS from structures located earlier along the reaction coordinate, differential metal coordination, and on barrier differences with two different cations.

Many-body exchange-repulsion in polarizable molecular mechanics. I. Orbital-based approximations and applications to hydrated metal cation complexes.

We have quantified the extent of the nonadditivity of the short‐range exchange‐repulsion energy, Eexch‐rep, in several polycoordinated complexes of alkali, alkaline‐earth, transition, and metal cations. This was done by performing ab initio energy decomposition analyses of interaction energies in these complexes. The magnitude of Eexch‐rep(n‐body, n > 2) was found to be strongly cation‐dependent, ranging from close to zero for some alkali metal complexes to about 6 kcal/mol for the hexahydrated Zn2+ complex. In all cases, the cation–water molecules, Eexch‐rep(three‐body), has been found to be the dominant contribution to many‐body exchange‐repulsion effects, higher order terms being negligible. As the physical basis of this effect is discussed, a three‐center exponential term was introduced in the SIBFA (Sum of Interactions Between Fragments Ab initio computed) polarizable molecular mechanics procedure to model such effects. The three‐body correction is added to the two‐center (two‐body) overlap‐like formulation of the short‐range repulsion contribution, Erep, which is grounded on simplified integrals obtained from localized molecular orbital theory. The present term is computed on using mostly precomputed two‐body terms and, therefore, does not increase significantly the computational cost of the method. It was shown to match closely Ethree‐body in a series of test cases bearing on the complexes of Ca2+, Zn2+, and Hg2+. For example, its introduction enabled to restore the correct tetrahedral versus square planar preference found from quantum chemistry calculations on the tetrahydrate of Hg2+ and [Hg(H2O)4]2+.

Electron Pair Localization Function (EPLF) for Density Functional Theory and ab Initio Wave Function-Based Methods: A New Tool for Chemical Interpretation

We present a modified definition of the Electron Pair Localization Function (EPLF), initially defined within the framework of quantum Monte Carlo approaches [ Scemama , A. ; Caffarel , M. ; Chaquin , P. J. Chem. Phys. 2004 , 121 , 1725 ] to be used in Density Functional Theories (DFT) and ab initio wave-function-based methods. This modified version of the EPLF-while keeping the same physical and chemical contents-is built to be analytically computable with standard wave functions or Kohn-Sham representations. It is illustrated that the EPLF defines a simple and powerful tool for chemical interpretation via selected applications including atomic and molecular closed-shell systems, σ and π bonds, radical and singlet open-shell systems, and molecules having a strong multiconfigurational character. Some applications of the EPLF are presented at various levels of theory and compared to Becke and Edgecombes Electron Localization Function (ELF). Our open-source parallel software implementation of the EPLF opens the possibility of its use by a large community of chemists interested in the chemical interpretation of complex electronic structures.

Impact of functionalized linkers on the energy landscape of ZIFs

Zeolitic imidazolate frameworks (ZIFs) are well-known for their thermal and chemical stability, as well as for their structural diversity reminiscent of those found in the realm of zeolites. Linker–linker interactions were recognized as essential in the discovery of new topologies through the choice of substituted imidazolates. However, the impact of the linker through modification of the imidazolates substituents on the energy landscape of ZIFs remains to be rationalized. In this work, LiB-based ZIFs serve as model crystal structures to explore the impact of linker–linker interactions, varying the number and position of methyl groups. The study focuses on the characteristics of experimental and hypothetical structures studied by first principle DFT-D calculations, and further interpreted through QSPR and Non covalent interaction (NCI) analysis. We provide an empirical QSPR model accounting for linker and topology effects on the stability of the frameworks. Both the position and number of substituents on the imidazolate linkers have a profound impact on the energy landscape of ZIFs, reshuffling the ranking of stabilized versus less stable topologies that were otherwise almost isoenergetic with unsubstituted imidazolate. NCI analysis revealed that methyl substituents induce repulsive interactions within the boron-centred cluster that are compensated by attractive non-bonded interactions at the larger scale of the solid. Besides the kinetic factors at play in ZIF synthesis which are difficult to consider from a modelling perspective, our calculations show that thermodynamic considerations are at work, explaining the intractability of certain topologies with certain linkers. Our calculations provide insight into the magnitude of the thermodynamic penalties that must be overcome in order to form particular topologies and the energy scale that needs to be overcome to generate lower density materials – a target for many experimental groups. The identified dominant linker–linker interactions could be exploited to overcome the limitations of current synthesis techniques.

Catalytic mechanism of 4-oxalocrotonate tautomerase: significances of protein-protein interactions on proton transfer pathways.

4-Oxalocrotonate tautomerase (4-OT), a member of tautomerase superfamily, is an essential enzyme in the degradative metabolism pathway occurring in the Krebs cycle. The proton transfer process catalyzed by 4-OT has been explored previously using both experimental and theoretical methods; however, the elaborate catalytic mechanism of 4-OT still remains unsettled. By combining classical molecular mechanics with quantum mechanics, our results demonstrate that the native hexametric 4-OT enzyme, including six protein monomers, must be employed to simulate the proton transfer process in 4-OT due to protein-protein steric and electrostatic interactions. As a consequence, only three out of the six active sites in the 4-OT hexamer are observed to be occupied by three 2-oxo-4-hexenedioates (2o4hex), i.e., half-of-the-sites occupation. This agrees with experimental observations on negative cooperative effect between two adjacent substrates. Two sequential proton transfers occur: one proton from the C3 position of 2o4hex is initially transferred to the nitrogen atom of the general base, Pro1. Subsequently, the same proton is shuttled back to the position C5 of 2o4hex to complete the proton transfer process in 4-OT. During the catalytic reaction, conformational changes (i.e., 1-carboxyl group rotation) of 2o4hex may occur in the 4-OT dimer model but cannot proceed in the hexametric structure. We further explained that the docking process of 2o4hex can influence the specific reactant conformations and an alternative substrate (2-hydroxymuconate) may serve as reactant under a different reaction mechanism than 2o4hex.

A complete NCI perspective: from new bonds to reactivity

The Non-Covalent Interaction (NCI) index is a new topological tool that has recently been added to the theoretical chemist’s arsenal. NCI fills a gap that existed within topological methods for the visualization of non-covalent interactions. Based on the electron density and its derivatives, it is able to reveal both attractive and repulsive interactions in the shape of isosurfaces, whose color code reveals the nature of the interaction. It is interesting to note that NCI can even be calculated at the promolecular level, making it a suitable tool for big systems, such as proteins or DNA. Within this chapter we will review the main characteristics of NCI, its similarities with and differences from previous approaches. Special attention will be paid to the visualization of new interaction types. Being based on the electron density, NCI is not only very stable with respect to the calculation method, but it is also a suitable tool for detecting new bonding mechanisms, since all such mechanisms should have a detectable effect on the electron density. This type of approach overcomes the limitations of bond definition, revealing all interaction types, irrespective of whether they have a name or have previously been identified. Finally, we will show how this tool can be used to understand chemical change along a chemical reaction. We will show an example of torquoselectivity and put forward an explanation of selectivity based on secondary interactions which is complementary to the historical orbital approach.

Pseudobond parameters for QM/MM studies involving nucleosides, nucleotides, and their analogs

In biological systems involving nucleosides, nucleotides, or their respective analogs, the ribose sugar moiety is the most common reaction site, for example, during DNA replication and repair. However, nucleic bases, which comprise a sizable portion of nucleotide molecules, are usually unreactive during such processes. In quantum mechanical∕molecular simulations of nucleic acid reactivity, it may therefore be advantageous to describe specific ribosyl or ribosyl phosphate groups quantum mechanically and their respective nucleic bases with a molecular mechanics potential function. Here, we have extended the pseudobond approach to enable quantum mechanical∕molecular mechanical simulations involving nucleotides, nucleosides, and their analogs in which the interface between the two subsystems is located between the sugar and the base, namely, the C(sp(3))-N(sp(2)) bond. The pseudobond parameters were optimized on a training set of 10 molecules representing several nucleotide and nucleoside bases and analogs, and they were then tested on a larger test set of 20 diverse molecules. Particular emphasis was placed on providing accurate geometries and electrostatic properties, including electrostatic potential, natural bond orbital (NBO) and atoms in molecules (AIM) charges and AIM first moments. We also tested the optimized parameters on five nucleotide and nucleoside analogues of pharmaceutical relevance and a small polypeptide (triglycine). Accuracy was maintained for these systems, which highlights the generality and transferability of the pseudobond approach.

Theoretical proposal for an organometallic route to cis-peptides

We show by means of quantum chemistry calculations that organolanthanide catalysis can be a way to obtain cis-amide bonds, thus providing clues for the synthesis of new peptidic materials.

Addressing the issues of non-isotropy and non-additivity in the development of quantum chemistry-grounded polarizable molecular mechanics.

We review two essential features of the intermolecular interaction energies (ΔE) computed in the context of quantum chemistry (QC): non-isotropy and non-additivity. Energy-decomposition analyses show the extent to which each comes into play in the separate ΔE contributions, namely electrostatic, short-range repulsion, polarization, charge-transfer and dispersion. Such contributions have their counterparts in anisotropic, polarizable molecular mechanics (APMM), and each of these should display the same features as in QC. We review examples to evaluate the performances of APMM in this respect. They bear on the complexes of one or several ligands with metal cations, and on multiply H-bonded complexes. We also comment on the involvement of polarization, a key contributor to non-additivity, in the issues of multipole transferability and conjugation. In the last section we provide recent examples of APMM validations by QC, which relate to interactions taking place in the recognition sites of kinases and metalloproteins. We conclude by mentioning prospects of extensive applications of APMM.