Shearing friction behaviour of synthetic polymers compared to a functionalized polysaccharide on biomimetic surfaces: models for the prediction of performance of eco-designed formulations.

The substitution of natural, bio-based and/or biodegradable polymers for those of petrochemical origin in consumer formulations has become an active area of research and development as the sourcing and destiny of material components becomes a more critical factor in product design. These polymers often differ from their petroleum-based counterparts in topology, raw material composition and solution behaviour. Effective and efficient reformulation that maintains comparable cosmetic performance to existing products requires a deep understanding of the differences in frictional behaviour between polymers as a function of their molecular structure. In this work, we simulate the tribological behaviour of three topologically distinct polymers in solution with surfactants and in contact with hair-biomimetic patterned surfaces. We compare a generic functionalized polysaccharide to two performant polymers used in shampoo formulations: a strongly positively charged polyelectrolyte and a zwitterionic copolymer. Topological differences are expected to affect rheological properties, as well as their direct interaction with structured biological substrates. Using a refined Martini-style coarse-grained model we describe the polymer-dependent differences in aggregation behaviour as well as selective interactions with a biomimetic model hair surface. Additionally, we introduce a formalism to characterize the response of the solution to shear as an initial study on lubrication properties, which define the sensorial performance of these systems in cosmetics (i.e., manageability, touch, etc.). The tools and techniques presented in this work illustrate the strength of molecular simulation in eco-design of formulation as a complement to experiment. These efforts help advance our understanding of how we can relate complex atomic-scale solution behaviour to relevant macroscopic properties. We expect these techniques to play an increasingly important role in advancing strategies for green polymer formulation design by providing an understanding for how new polymers could reach and even exceed the level of performance of existing polymers.

S/G-1: an ab initio force-field blending frozen Hermite Gaussian densities and distributed multipoles. Proof of concept and first applications to metal cations.

We demonstrate as a proof of principle the capabilities of a novel hybrid MM'/MM polarizable force field to integrate short-range quantum effects in molecular mechanics (MM) through the use of Gaussian electrostatics. This lead to a further gain in accuracy in the representation of the first coordination shell of metal ions. It uses advanced electrostatics and couples two point dipole polarizable force fields, namely, the Gaussian electrostatic model (GEM), a model based on density fitting, which uses fitted electronic densities to evaluate nonbonded interactions, and SIBFA (sum of interactions between fragments ab initio computed), which resorts to distributed multipoles. To understand the benefits of the use of Gaussian electrostatics, we evaluate first the accuracy of GEM, which is a pure density-based Gaussian electrostatics model on a test Ca(II)-H2O complex. GEM is shown to further improve the agreement of MM polarization with ab initio reference results. Indeed, GEM introduces nonclassical effects by modeling the short-range quantum behavior of electric fields and therefore enables a straightforward (and selective) inclusion of the sole overlap-dependent exchange-polarization repulsive contribution by means of a Gaussian damping function acting on the GEM fields. The S/G-1 scheme is then introduced. Upon limiting the use of Gaussian electrostatics to metal centers only, it is shown to be able to capture the dominant quantum effects at play on the metal coordination sphere. S/G-1 is able to accurately reproduce ab initio total interaction energies within closed-shell metal complexes regarding each individual contribution including the separate contributions of induction, polarization, and charge-transfer. Applications of the method are provided for various systems including the HIV-1 NCp7-Zn(II) metalloprotein. S/G-1 is then extended to heavy metal complexes. Tested on Hg(II) water complexes, S/G-1 is shown to accurately model polarization up to quadrupolar response level. This opens up the possibility of embodying explicit scalar relativistic effects in molecular mechanics thanks to the direct transferability of ab initio pseudopotentials. Therefore, incorporating GEM-like electron density for a metal cation enable the introduction of nonambiguous short-range quantum effects within any point-dipole based polarizable force field without the need of an extensive parametrization.

Revisiting H2O Nucleation around Au+ and Hg2+: The Peculiar "Pseudo-Soft" Character of the Gold Cation.

In this contribution, we propose a deeper understanding of the electronic effects affecting the nucleation of water around the Au+ and Hg2+ metal cations using quantum chemistry. To do so, and in order to go beyond usual energetical studies, we make extensive use of state of the art quantum interpretative techniques combining ELF/NCI/QTAIM/EDA computations to capture all ranges of interactions stabilizing the well characterized microhydrated structures. The Electron Localization Function (ELF) topological analysis reveals the peculiar role of the Au+ outer-shell core electrons (subvalence) that appear already spatially preorganized once the addition of the first water molecule occurs. Thus, despite the addition of other water molecules, the electronic structure of Au(H2O)+ appears frozen due to relativistic effects leading to a maximal acceptation of only two waters in gold's first hydration shell. As the values of the QTAIM (Quantum Theory of Atoms in Molecules) cations's charge is discussed, the Non Covalent Interactions (NCI) analysis showed that Au+ appears still able to interact through longer range van der Waals interaction with the third or fourth hydration shell water molecules. As these types of interaction are not characteristic of either a hard or soft metal cation, we introduced the concept of a "pseudo-soft" cation to define Au+ behavior. Then, extending the study, we performed the same computations replacing Au+ with Hg2+, an isoelectronic cation. If Hg2+ behaves like Au+ for small water clusters, a topological, geometrical, and energetical transition appears when the number of water molecules increases. Regarding the HSAB theory, this transition is characteristic of a shift of Hg2+ from a pseudosoft form to a soft ion and appears to be due to a competition between the relativistic and correlation effects. Indeed, if relativistic effects are predominant, then mercury will behave like gold and have a similar subvalence/geometry; otherwise when correlation effects are predominant, Hg2+ behaves like a soft cation.

Nonclassical CH-π supramolecular interactions in artemisinic acid favor a single conformation, yielding high diastereoselectivity in the reduction with diazene.

The high diastereoselectivity of the hydrogenation of artemisinate by diazene to form dihydroartemisinate (diastereoselective ratio, dr, 97:3) necessary for efficient production of artemisin has been rationalized by state-of-the-art DFT calculations and identification of the noncovalent interactions by coupled ELF/NCI analysis. Remarkably, a single conformer of artemisinate is responsible for the high diastereoselectivity of the reaction. NMR studies confirm the preference for a single conformation that is found to be identical to that predicted by the calculations. The calculations and ELF/NCI analyses show that the hydrogenation of the exocyclic activated C═C double bond has a low energy barrier and that the lowest transition state and the preferred conformation of free artemisinate develop the same network of weak noncovalent interactions between the electron donor groups (oxygen and exocyclic C═C double bond) and CH bonds of the cis-decalene group of the artemisinate, which rationalize the high diastereoselectivity unusual for a strongly exothermic reaction.

Noncovalent Interaction Analysis in Fluctuating Environments.

Noncovalent interactions play a central role in many chemical and biological systems. In a previous study, Johnson et al developed a NonCovalent Interaction (NCI) index to characterize and visualize different types of weak interactions. To apply the NCI analysis to fluctuating environments as in solution phase, we here develop a new Averaged NonCovalent Interaction (i.e., aNCI) index along with a fluctuation index to characterize magnitude of interactions and fluctuations. We applied aNCI for various systems including solute-solvent and ligand-protein noncovalent interactions. For water and benzene molecules in aqueous solution, solvation structures and the specific hydrogen bond patterns were visualized clearly. For the Cl-+CH3Cl SN2 reaction in aqueous solution, charge reorganization influences over solvation structure along SN2 reaction were revealed. For ligand-protein systems, aNCI can recover several key fluctuating hydrogen bond patterns that have potential applications for drug design. Therefore, aNCI, as a complementary approach to the original NCI method, can extract and visualize noncovalent interactions from thermal noise in fluctuating environments.

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.

QM/MM modelling of ketosteroid isomerase reactivity indicates that active site closure is integral to catalysis.

Ketosteroid isomerase (Δ5-3-keto steroid isomerase or steroid Δ-isomerase) is a highly efficient enzyme at the centre of current debates on enzyme catalysis. We have modelled the reaction mechanism of the isomerization of 3-oxo-Δ5-steroids into their Δ4-conjugated isomers using high-level combined quantum mechanics/molecular mechanics (QM/MM) methods, and semi-empirical QM/MM molecular dynamics simulations. Energy profiles were obtained at various levels of QM theory (AM1, B3LYP and SCS-MP2). The high-level QM/MM profile is consistent with experimental data. QM/MM dynamics simulations indicate that active site closure and desolvation of the catalytic Asp38 occur before or during formation of dienolate intermediates. These changes have a significant effect on the reaction barrier. A low barrier to reaction is found only when the active site is closed, poising it for catalysis. This conformational change is thus integral to the whole process. The effects on the barrier are apparently largely due to changes in solvation. The combination of high-level QM/MM energy profiles and QM/MM dynamics simulation shows that the reaction involves active site closure, desolvation of the catalytic base, efficient isomerization and re-opening of the active site. These changes highlight the transition between the ligand binding/releasing form and the catalytic form of the enzyme. The results demonstrate that electrostatic interactions (as a consequence of pre-organization of the active site) are crucial for stabilization during the chemical reaction step, but closure of the active site is essential for efficient catalysis to occur.

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.

Coupling quantum interpretative techniques: another look at chemical mechanisms in organic reactions.

A cross ELF-NCI analysis is tested over prototypical organic reactions. The synergetic use of ELF and NCI enables the understanding of reaction mechanisms since each method can respectively identify regions of strong and weak electron pairing. Chemically intuitive results are recovered and enriched by the identification of new features. Non covalent interactions are found to foresee the evolution of the reaction from the initial steps. Within NCI, no topological catastrophe is observed as changes are continuous to such an extent that future reaction steps can be predicted from the evolution of the initial NCI critical points. Indeed, strong convergences through the reaction paths between ELF and NCI critical points enable to identify key interactions at the origin of the bond formation. VMD scripts enabling the automatic generation of movies depicting the cross NCI/ELF analysis along a reaction path (or following a Born-Oppenheimer molecular dynamics trajectory) are provided as S.I.

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.

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, E(exch-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 E(exch-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 Zn(2+) complex. In all cases, the cation-water molecules, E(exch-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, E(rep), 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 E(three-body) in a series of test cases bearing on the complexes of Ca(2+), Zn(2+), and Hg(2+). For example, its introduction enabled to restore the correct tetrahedral versus square planar preference found from quantum chemistry calculations on the tetrahydrate of Hg(2+) and [Hg(H(2)O)(4)](2+).

Correlation between electron localization and metal ion mutagenicity in DNA synthesis from QM/MM calculations.

DNA polymerases require two divalent metal ions in the active site for catalysis. Mg(2+) has been confirmed to be the most probable cation utilized by most polymerases in vivo. Other metal ions are either potent mutagens or inhibitors. We used structural and topological analyses based on ab initio QM/MM calculations to study human DNA polymerase λ (Polλ) with different metals in the active site. Our results indicate a slightly longer O3'-Pα distance (∼3.6 Å) for most inhibitor cations compared to the natural and mutagenic metals (∼3.3-3.4 Å). Optimization with a larger basis set for the previously reported transition state (TS) structures (Cisneros et al., DNA Repair, 2008, 7, 1824.) gives barriers of 17.4 kcal mol(-1) and 15.1 kcal mol(-1) for the Mg(2+) and Mn(2+) catalyzed reactions respectively. Relying on the key relation between the topological signature of a metal cation and its selectivity within biological systems (de Courcy et al., J. Chem. Theor. Comput., 2010, 6, 1048.) we have performed electron localization function (ELF) topological analyses. These analyses show that all inhibitor and mutagenic metals considered, except Na(+), present a "split" of the outer-shell density of the metal. This "splitting" is not observed for the non-mutagenic Mg(2+) metal. Population and multipole analyses on the ELF basins reveal that the electronic dipolar and quadrupolar polarization is significantly different with Mg(2+) compared to all other cations. Our results shed light at the atomic level on the subtle differences between Mg(2+), mutagenic, and inhibitor metals in DNA polymerases. These results provide a correlation between the electronic distribution of the cations in the active site and the possible consequences on DNA synthesis.

NCIPLOT: a program for plotting non-covalent interaction regions.

Non-covalent interactions hold the key to understanding many chemical, biological, and technological problems. Describing these non-covalent interactions accurately, including their positions in real space, constitutes a first step in the process of decoupling the complex balance of forces that define non-covalent interactions. Because of the size of macromolecules, the most common approach has been to assign van der Waals interactions (vdW), steric clashes (SC), and hydrogen bonds (HBs) based on pairwise distances between atoms according to their van der Waals radii. We recently developed an alternative perspective, derived from the electronic density: the Non-Covalent Interactions (NCI) index [J. Am. Chem. Soc. 2010, 132, 6498]. This index has the dual advantages of being generally transferable to diverse chemical applications and being very fast to compute, since it can be calculated from promolecular densities. Thus, NCI analysis is applicable to large systems, including proteins and DNA, where analysis of non-covalent interactions is of great potential value. Here, we describe the NCI computational algorithms and their implementation for the analysis and visualization of weak interactions, using both self-consistent fully quantum-mechanical, as well as promolecular, densities. A wide range of options for tuning the range of interactions to be plotted is also presented. To demonstrate the capabilities of our approach, several examples are given from organic, inorganic, solid state, and macromolecular chemistry, including cases where NCI analysis gives insight into unconventional chemical bonding. The NCI code and its manual are available for download at http://www.chem.duke.edu/~yang/software.htm.

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 Edgecombe's 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.

Polarizable molecular dynamics simulation of Zn(II) in water using the AMOEBA force field.

The hydration free energy, structure, and dynamics of the zinc divalent cation are studied using a polarizable force field in molecular dynamics simulations. Parameters for the Zn(2+) are derived from gas-phase ab initio calculation of Zn(2+)-water dimer. The Thole-based dipole polarization is adjusted based on the Constrained Space Orbital Variations (CSOV) calculation while the Symmetry Adapted Perturbation Theory (SAPT) approach is also discussed. The vdW parameters of Zn(2+) have been obtained by comparing the AMOEBA Zn(2+)-water dimerization energy with results from several theory levels and basis sets over a range of distances. Molecular dynamics simulations of Zn(2+) solvation in bulk water are subsequently performed with the polarizable force field. The calculated first-shell water coordination number, water residence time and free energy of hydration are consistent with experimental and previous theoretical values. The study is supplemented with extensive Reduced Variational Space (RVS) and Electron Localization Function (ELF) computations in order to unravel the nature of the bonding in Zn(2+)(H(2)O)(n) (n=1,6) complexes and to analyze the charge transfer contribution to the complexes. Results show that the importance of charge transfer decreases as the size of Zn-water cluster grows due to anticooperativity and to changes in the nature of the metal-ligand bonds. Induction could be dominated by polarization when the system approaches condensed-phase and the covelant effects are eliminated from the Zn(II)-water interaction. To construct an "effective" classical polarizable potential for Zn(2+) in bulk water, one should therefore avoid over-fitting to the ab initio charge transfer energy of Zn(2+)-water dimer. Indeed, in order to avoid overestimation of condensed-phase many-body effects, which is crucial to the transferability of polarizable molecular dynamics, charge transfer should not be included within the classical polarization contribution and should preferably be either incorporated in to the pairwise van der Waals contribution or treated explicitly.