Complexes of thiomandelate and captopril mercaptocarboxylate inhibitors to metallo-beta-lactamase by polarizable molecular mechanics. Validation on model binding sites by quantum chemistry

Using the polarizable molecular mechanics method SIBFA, we have performed a search for the most stable binding modes of D- and L-thiomandelate to a 104-residue model of the metallo-beta-lactamase from B. fragilis, an enzyme involved in the acquired resistance of bacteria to antibiotics. Energy balances taking into account solvation effects computed with a continuum reaction field procedure indicated the D-isomer to be more stably bound than the L-one, conform to the experimental result. The most stably bound complex has the S(-) ligand bridging monodentately the two Zn(II) cations and one carboxylate O(-) H-bonded to the Asn193 side chain. We have validated the SIBFA energy results by performing additional SIBFA as well as quantum chemical (QC) calculations on small (88 atoms) model complexes extracted from the 104-residue complexes, which include the residues involved in inhibitor binding. Computations were done in parallel using uncorrelated (HF) as well as correlated (DFT, LMP2, MP2) computations, and the comparisons extended to corresponding captopril complexes (Antony et al., J Comput Chem 2002, 23, 1281). The magnitudes of the SIBFA intermolecular interaction energies were found to correctly reproduce their QC counterparts and their trends for a total of twenty complexes.     

Calibration of the dianionic phosphate group: Validation on the recognition site of the homodimeric enzyme phosphoglucose isomerase

We calibrate and validate the parameters necessary to represent the dianionic phosphate group (DPG) in molecular mechanics. DPG is an essential fragment of signaling biological molecules and protein-binding ligands. It is a constitutive fragment of biosensors, which bind to the dimer interface of phosphoglucose isomerase (PGI), an intracellular enzyme involved in sugar metabolism, as well as an extracellular protein known as autocrine motility factor (AMF) closely related to metastasis formation. Our long-term objective is to design DPG-based biosensors with enhanced affinities for AMF/PGI cancer biomarker in blood. Molecular dynamics with polarizable potentials could be used toward this aim. This requires to first evaluate the accuracy of such potentials upon representing the interactions of DPG with its PGI ligands and tightly bound water molecules. Such evaluations are done by comparisons with high-level ab initio quantum chemistry (QC) calculations. We focus on the Sum of Interactions Between Fragments Ab initio computed (SIBFA) polarizable molecular mechanics procedure. We present first the results of the DPG calibration. This is followed by comparisons between ΔE(SIBFA) and ΔE(QC) regarding bi-molecular complexes of DPG with the main-chain and side-chain PGI residues, which bind to it in the recognition site. We then consider DPG complexes with an increasing number of PGI residues. The largest QC complexes encompass the entirety of the recognition site, with six structural water molecules totaling up to 211 atoms. A persistent and satisfactory agreement could be shown between ΔE(SIBFA) and ΔE(QC). These validations constitute an essential first step toward large-scale molecular dynamics simulations of DPG-based biosensors bound at the PGI dimer interface. © 2020 Wiley Periodicals, Inc.     

Could an anisotropic molecular mechanics/dynamics potential account for sigma hole effects in the complexes of halogenated compounds?

Halogenated compounds are gaining an increasing importance in medicinal chemistry and materials science. Ab initio quantum chemistry (QC) has unraveled the existence of a “sigma hole” along the C? X (X = F, Cl, Br, I) bond, namely, a depletion of electronic density prolonging the bond, concomitant with a build‐up on its sides, both of which are enhanced along the F < Cl < Br < I series. We have evaluated whether these features were intrinsically built‐in in an anisotropic, polarizable molecular mechanics (APMM) procedure such as SIBFA (sum of interactions between fragments ab initio computed). For that purpose, we have computed the interaction energies of fluoro‐, chloro‐, and bromobenzene with two probes: a divalent cation, Mg(II), and water approaching X through either one H or its O atom. This was done by parallel QC energy‐decomposition analyses (EDA) and SIBFA computations. With both probes, the leading QC contribution responsible for the existence of the sigma hole is the Coulomb contribution E_c. For all three halogenated compounds, and with both probes, the in‐ and out‐of‐plane angular features of E_c were closely mirrored by the SIBFA electrostatic multipolar contribution (E_MTP). Resorting to such a contribution thus dispenses with empirically‐fitted “extra”, off‐centered partial atomic charges as in classical molecular mechanics/dynamics. © 2013 Wiley Periodicals, Inc.     

Quantum‐chemistry based calibration of the alkali metal cation series (Li+Cs+) for large‐scale polarizable molecular mechanics/dynamics simulations

The alkali metal cations in the series Li⁺? Cs⁺ act as major partners in a diversity of biological processes and in bioinorganic chemistry. In this article, we present the results of their calibration in the context of the SIBFA polarizable molecular mechanics/dynamics procedure. It relies on quantum‐chemistry (QC) energy‐decomposition analyses of their monoligated complexes with representative O? , N? , S? , and Se? ligands, performed with the aug‐cc‐pVTZ(‐f) basis set at the Hartree–Fock level. Close agreement with QC is obtained for each individual contribution, even though the calibration involves only a limited set of cation‐specific parameters. This agreement is preserved in tests on polyligated complexes with four and six O? ligands, water and formamide, indicating the transferability of the procedure. Preliminary extensions to density functional theory calculations are reported.     

Complexes of a Zn‐metalloenzyme binding site with hydroxamate‐containing ligands. A case for detailed benchmarkings of polarizable molecular mechanics/dynamics potentials when the experimental binding structure is unknown

Zn‐metalloproteins are a major class of targets for drug design. They constitute a demanding testing ground for polarizable molecular mechanics/dynamics aimed at extending the realm of quantum chemistry (QC) to very long‐duration molecular dynamics (MD). The reliability of such procedures needs to be demonstrated upon comparing the relative stabilities of competing candidate complexes of inhibitors with the recognition site stabilized in the course of MD. This could be necessary when no information is available regarding the experimental structure of the inhibitor–protein complex. Thus, this study bears on the phosphomannose isomerase (PMI) enzyme, considered as a potential therapeutic target for the treatment of several bacterial and parasitic diseases. We consider its complexes with 5‐phospho‐d ‐arabinonohydroxamate and three analog ligands differing by the number and location of their hydroxyl groups. We evaluate the energy accuracy expectable from a polarizable molecular mechanics procedure, SIBFA. This is done by comparisons with ab initio quantum‐chemistry (QC) calculations in the following cases: (a) the complexes of the four ligands in three distinct structures extracted from the entire PMI‐ligand energy‐minimized structures, and totaling up to 264 atoms; (b) the solvation energies of several energy‐minimized complexes of each ligand with a shell of 64 water molecules; (c) the conformational energy differences of each ligand in different conformations characterized in the course of energy‐minimizations; and (d) the continuum solvation energies of the ligands in different conformations. The agreements with the QC results appear convincing. On these bases, we discuss the prospects of applying the procedure to ligand‐macromolecule recognition problems. © 2016 Wiley Periodicals, Inc.     

Quantum mechanics/molecular mechanics electrostatic embedding with continuous and discrete functions

A quantum mechanics/molecular mechanics (QM/MM) implementation that uses the Gaussian electrostatic model (GEM) as the MM force field is presented. GEM relies on the reproduction of electronic density by using auxiliary basis sets to calculate each component of the intermolecular interaction. This hybrid method has been used, along with a conventional QM/MM (point charges) method, to determine the polarization on the QM subsystem by the MM environment in QM/MM calculations on 10 individual H(2)O dimers and a Mg(2+)-H(2)O dimer. We observe that GEM gives the correct polarization response in cases when the MM fragment has a small charge, while the point charges produce significant over-polarization of the QM subsystem and in several cases present an opposite sign for the polarization contribution. In the case when a large charge is located in the MM subsystem, for example, the Mg(2+) ion, the opposite is observed at small distances. However, this is overcome by the use of a damped Hermite charge, which provides the correct polarization response.     

Representation of Zn(II) complexes in polarizable molecular mechanics. Further refinements of the electrostatic and short-range contributions. Comparisons with parallel ab initio computations

We present refinements of the SIBFA molecular mechanics procedure to represent the intermolecular interaction energies of Zn(II). The two first-order contributions, electrostatic (E(MTP)), and short-range repulsion (E(rep)), are refined following the recent developments due to Piquemal et al. (Piquemal et al. J Phys Chem A 2003, 107, 9800; and Piquemal et al., submitted). Thus, E(MTP) is augmented with a penetration component, E(pen), which accounts for the effects of reduction in electronic density of a given molecular fragment sensed by another interacting fragment upon mutual overlap. E(pen) is fit in a limited number of selected Zn(II)-mono-ligated complexes so that the sum of E(MTP) and E(pen) reproduces the Coulomb contribution E(c) from an ab initio Hartree-Fock energy decomposition procedure. Denoting by S, the overlap matrix between localized orbitals on the interacting monomers, and by R, the distance between their centroids, E(rep) is expressed by a S(2)/R term now augmented with an S(2)/R(2) one. It is calibrated in selected monoligated Zn(II) complexes to fit the corresponding exchange repulsion E(exch) from ab initio energy decomposition, and no longer as previously the difference between (E(c) + E(exch)) and E(MTP). Along with the reformulation of the first-order contributions, a limited recalibration of the second-order contributions was carried out. As in our original formulation (Gresh, J Comput Chem 1995, 16, 856), the Zn(II) parameters for each energy contribution were calibrated to reproduce the radial behavior of its ab initio HF counterpart in monoligated complexes with N, O, and S ligands. The SIBFA procedure was subsequently validated by comparisons with parallel ab initio computations on several Zn(II) polyligated complexes, including binuclear Zn(II) complexes as in models for the Gal4 and beta-lactamase metalloproteins. The largest relative error with respect to the RVS computations is 3%, and the ordering in relative energies of competing structures reproduced even though the absolute numerical values of the ab initio interaction energies can be as large as 1220 kcal/mol. A term-to-term identification of the SIBFA contributions to their ab initio counterparts remained possible even for the largest sized complexes.     

Inclusion of the ligand field contribution in a polarizable molecular mechanics: SIBFA-LF

To account for the distortion of the coordination sphere that takes place in complexes containing open-shell metal cations such as Cu(II), we implemented, in sum of interactions between fragments ab initio computed (SIBFA) molecular mechanics, an additional contribution to take into account the ligand field splitting of the metal d orbitals. This term, based on the angular overlap model, has been parameterized for Cu(II) coordinated to oxygen and nitrogen ligands. The comparison of the results obtained from density functional theory computations on the one hand and SIBFA or SIBFA-LF on the other shows that SIBFA-LF gives geometric arrangements similar to those obtained from quantum mechanical computations. Moreover, the geometric improvement takes place without downgrading the energetic agreement obtained from SIBFA. The systems considered are Cu(II) interacting with six water molecules, four ammonia or four imidazoles, and four water plus two formate anions.     

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+).     

Towards a force field based on density fitting

Total intermolecular interaction energies are determined with a first version of the Gaussian electrostatic model (GEM-0), a force field based on a density fitting approach using s-type Gaussian functions. The total interaction energy is computed in the spirit of the sum of interacting fragment ab initio (SIBFA) force field by separately evaluating each one of its components: electrostatic (Coulomb), exchange repulsion, polarization, and charge transfer intermolecular interaction energies, in order to reproduce reference constrained space orbital variation (CSOV) energy decomposition calculations at the B3LYP/aug-cc-pVTZ level. The use of an auxiliary basis set restricted to spherical Gaussian functions facilitates the rotation of the fitted densities of rigid fragments and enables a fast and accurate density fitting evaluation of Coulomb and exchange-repulsion energy, the latter using the overlap model introduced by Wheatley and Price [Mol. Phys. 69, 50718 (1990)]. The SIBFA energy scheme for polarization and charge transfer has been implemented using the electric fields and electrostatic potentials generated by the fitted densities. GEM-0 has been tested on ten stationary points of the water dimer potential energy surface and on three water clusters (n = 16,20,64). The results show very good agreement with density functional theory calculations, reproducing the individual CSOV energy contributions for a given interaction as well as the B3LYP total interaction energies with errors below kBT at room temperature. Preliminary results for Coulomb and exchange-repulsion energies of metal cation complexes and coupled cluster singles doubles electron densities are discussed.     

Halogen bonding in ligand-receptor systems in the framework of classical force fields

Halogen bond is an important non-covalent interaction which is receiving a growing attention in the study of protein-ligand complexes. Many drugs are halogenated molecules and it has been recently shown that many halogenated ligands establish halogen bonds with biomolecules. As the halogen bond nature is due to an anisotropy of the electrostatic potential around halogen atoms, it is not possible to use traditional force fields based on a set of atom-centred charges to study halogen bonds in biomolecules. We show that the introduction of pseudo-atoms on halogens permits us to correctly describe the anisotropy of the electrostatic potential and to perform molecular dynamics simulations on complexes of proteins with halogenated ligands that reproduce experimental values. The results are compared with crystallographic data and with hybrid quantum mechanics/molecular mechanics calculations.     

Polarizable molecular mechanics studies of Cu(I)/Zn(II) superoxide dismutase: Bimetallic binding site and structured waters

The existence of a network of structured waters in the vicinity of the bimetallic site of Cu/Zn‐superoxide dismutase (SOD) has been inferred from high‐resolution X‐ray crystallography. Long‐duration molecular dynamics (MD) simulations could enable to quantify the lifetimes and possible interchanges of these waters between themselves as well as with a ligand diffusing toward the bimetallic site. The presence of several charged or polar ligands makes it necessary to resort to second‐generation polarizable potentials. As a first step toward such simulations, we benchmark in this article the accuracy of one such potential, sum of interactions between fragments Ab initio computed (SIBFA), by comparisons with quantum mechanics (QM) computations. We first consider the bimetallic binding site of a Cu/Zn‐SOD, in which three histidines and a water molecule are bound to Cu(I) and three histidines and one aspartate are bound to Zn(II). The comparisons are made for different His6 complexes with either one or both cations, and either with or without Asp and water. The total net charges vary from zero to three. We subsequently perform preliminary short‐duration MD simulations of 296 waters solvating Cu/Zn‐SOD. Six representative geometries are selected and energy‐minimized. Single‐point SIBFA and QM computations are then performed in parallel on model binding sites extracted from these six structures, each of which totals 301 atoms including the closest 28 waters from the Cu metal site. The ranking of their relative stabilities as given by SIBFA is identical to the QM one, and the relative energy differences by both approaches are fully consistent. In addition, the lowest‐energy structure, from SIBFA and QM, has a close overlap with the crystallographic one. The SIBFA calculations enable to quantify the impact of polarization and charge transfer in the ranking of the six structures. Five structural waters, which connect Arg141 and Glu131, are endowed with very high dipole moments (2.7–3.0 Debye), equal and larger than the one computed by SIBFA in ice‐like arrangements (2.7 D).     

Coupled semiempirical quantum mechanics and molecular mechanics (QM/MM) calculations on the aqueous solvation free energies of ionized molecules

The aqueous solvation free energies of ionized molecules were computed using a coupled quantum mechanical and molecular mechanical (QM/MM) model based on the AM1, MNDO, and PM3 semiempirical molecular orbital methods for the solute molecule and the TIP3P molecular mechanics model for liquid water. The present work is an extension of our model for neutral solutes where we assumed that the total free energy is the sum of components derived from the electrostatic/polarization terms in the Hamiltonian plus an empirical “nonpolar” term. The electrostatic/polarization contributions to the solvation free energies were computed using molecular dynamics (MD) simulation and thermodynamic integration techniques, while the nonpolar contributions were taken from the literature. The contribution to the electrostatic/polarization component of the free energy due to nonbonded interactions outside the cutoff radii used in the MD simulations was approximated by a Born solvation term. The experimental free energies were reproduced satisfactorily using variational parameters from the vdW terms as in the original model, in addition to a parameter from the one-electron integral terms. The new one-electron parameter was required to account for the short-range effects of overlapping atomic charge densities. The radial distribution functions obtained from the MD simulations showed the expected H-bonded structures between the ionized solute molecule and solvent molecules. We also obtained satisfactory results by neglecting both the empirical nonpolar term and the electronic polarization of the solute, i.e., by implementing a nonpolarization model. ©1999 John Wiley & Sons, Inc. J Comput Chem 20: 1028–1038, 1999     

Importance of explicit smeared lone‐pairs in anisotropic polarizable molecular mechanics. Torture track angular tests for exchange‐repulsion and charge transfer contributions

A correct representation of the short‐range contributions such as exchange‐repulsion (E _rep) and charge‐transfer (E _ct) is essential for the soundness of separable, anisotropic polarizable molecular mechanics potentials. Within the context of the SIBFA procedure, this is aimed at by explicit representations of lone pairs in their expressions. It is necessary to account for their anisotropic behaviors upon performing not only in‐plane, but also out‐of‐plane, variations of a probe molecule or cation interacting with a target molecule or molecular fragment. Thus, E _rep and E _ct have to reproduce satisfactorily the corresponding anisotropies of their quantum chemical (QC) counterparts. A significant improvement of the out‐of‐plane dependencies was enabled when the sp² and sp localized lone‐pairs are, even though to a limited extent, delocalized on both sides of the plane, above and below the atom bearer but at the closely similar angles as the in‐plane lone pair. We report calibration and validation tests on a series of monoligated complexes of a probe Zn(II) cation with several biochemically relevant ligands. Validations are then performed on several polyligated Zn(II) complexes found in the recognition sites of Zn‐metalloproteins. Such calibrations and validations are extended to representative monoligated and polyligated complexes of Mg(II) and Ca(II). It is emphasized that the calibration of all three cations was for each ΔE contribution done on a small training set bearing on a limited number of representative N , O , and S monoligated complexes. Owing to the separable nature of ΔE , a secure transferability is enabled to a diversity of polyligated complexes. For these the relative errors with respect to the target ΔE (QC) values are generally < 3%. Overall, the article proposes a full set of benchmarks that could be useful for force field developers. © 2017 Wiley Periodicals, Inc.     

Intramolecular interaction energies in model alanine and glycine tetrapeptides. Evaluation of anisotropy, polarization, and correlation effects. A parallel ab initio HF/MP2, DFT, and polarizable molecular mechanics study

An extension of the SIBFA polarizable molecular mechanics procedure to flexible oligopeptides is reported. The procedure is evaluated by computing the relative conformational energies, deltaE(conf), of the alanine tetrapeptide in 10 representative conformations, which were originally derived by Beachy et al. (J Am Chem Soc 1997, 119, 5908) to benchmark molecular mechanics procedures with respect to ab initio computations. In the present study, a particular emphasis is on the separable nature of the components of the energy and the particular impact of the polarization energy component on deltaE(conf). We perform comparisons with respect to single-point HF, DFT, LMP2, and MP2 computations done at the SIBFA-derived energy minima. Such comparisons are made first for the 10 conformers derived from phi/psi torsional angle energy-minimization (the rigid rotor approach), and, in a second step, after allowing additional relaxation of the C(alpha) centered valence angles. In both series of energy-minimization, the SIBFA deltaE(conf) compared best with the LMP2 results using the 6-311G** basis set, the rms being 1.3 kcal/mol. In the absence of the polarization component, the rms is 3.5 kcal/mol. In both series of minimizations, the magnitudes of deltaE(conf), computed as differences with respect to the most stable conformer taken as energy zero, decrease along the series: HF > DFT > LMP2 > SIBFA > MP2, indicative of increasing stabilization of the most highly folded conformers.     

Binding of 5-phospho-D-arabinonohydroxamate and 5-phospho-D-arabinonate inhibitors to zinc phosphomannose isomerase from Candida albicans studied by polarizable molecular mechanics and quantum mechanics

Type I phosphomannose isomerase (PMI) is a Zn-dependent metalloenzyme involved in the isomerization of D-fructose 6-phosphate to D-mannose 6-phosphate. One of our laboratories has recently designed and synthesized 5-phospho-D-arabinonohydroxamate (5PAH), an inhibitor endowed with a nanomolar affinity for PMI (Roux et al., Biochemistry 2004, 43, 2926). By contrast, the 5-phospho-D-arabinonate (5PAA), in which the hydroxamate moiety is replaced by a carboxylate one, is devoid of inhibitory potency. Subsequent biochemical studies showed that in its PMI complex, 5PAH binds Zn(II) through its hydroxamate moiety rather than through its phosphate. These results have stimulated the present theoretical investigation in which we resort to the SIBFA polarizable molecular mechanics procedure to unravel the structural and energetical aspects of 5PAH and 5PAA binding to a 164-residue model of PMI. Consistent with the experimental results, our theoretical studies indicate that the complexation of PMI by 5PAH is much more favorable than by 5PAA, and that in the 5PAH complex, Zn(II) ligation by hydroxamate is much more favorable than by phosphate. Validations by parallel quantum-chemical computations on model of the recognition site extracted from the PMI-inhibitor complexes, and totaling up to 140 atoms, showed the values of the SIBFA intermolecular interaction energies in such models to be able to reproduce the quantum-chemistry ones with relative errors < 3%. On the basis of the PMI-5PAH SIBFA energy-minimized structure, we report the first hypothesis of a detailed view of the active site of the zinc PMI complexed to the high-energy intermediate analogue inhibitor, which allows us to identify active site residues likely involved in the proton transfer between the two adjacent carbons of the substrates.     

Characterization and quantification of the role of coherence in ultrafast quantum biological experiments using quantum master equations,atomistic simulations,and quantum process tomography

Long-lived electronic coherences in various photosynthetic complexes at cryogenic and room temperature have generated vigorous efforts both in theory and experiment to understand their origins and explore their potential role to biological function. The ultrafast signals resulting from the experiments that show evidence for these coherences result from many contributions to the molecular polarization. Quantum process tomography (QPT) is a technique whose goal is that of obtaining the time-evolution of all the density matrix elements based on a designed set of experiments with different preparation and measurements. The QPT procedure was conceived in the context of quantum information processing to characterize and understand general quantum evolution of controllable quantum systems, for example while carrying out quantum computational tasks. We introduce our QPT method for ultrafast experiments, and as an illustrative example, apply it to a simulation of a two-chromophore subsystem of the Fenna-Matthews-Olson photosynthetic complex, which was recently shown to have long-lived quantum coherences. Our Fenna-Matthews-Olson model is constructed using an atomistic approach to extract relevant parameters for the simulation of photosynthetic complexes that consists of a quantum mechanics/molecular mechanics approach combined with molecular dynamics and the use of state-of-the-art quantum master equations. We provide a set of methods that allow for quantifying the role of quantum coherence, dephasing, relaxation and other elementary processes in energy transfer efficiency in photosynthetic complexes, based on the information obtained from the atomistic simulations, or, using QPT, directly from the experiment. The ultimate goal of the combination of this diverse set of methodologies is to provide a reliable way of quantifying the role of long-lived quantum coherences and obtain atomistic insight of their causes.     

层状双金属氢氧化物微观结构与性质的理论研究进展

总结了近年来理论计算方法在研究层状双金属氢氧化物(LDHs)结构与功能方面的应用现状. 结合LDHs材料的结构特点, 归纳了量子力学、分子力学、几何建模及物理静电模型相结合对LDHs材料进行结构模拟的思路, 比较了各种方法在LDHs结构模拟上的优势及存在的不足. 量子力学方法能够精确获得水滑石材料的层板构成及作用机制、简单阴离子插层水滑石主客体间的超分子作用实质以及电子性质、反应机理等方面的信息. 与量子力学相比较, 分子力学方法可以快速得到插层水滑石材料的层间阴离子排布及取向、水合膨胀特性及宏观力学性质等. 几何模型和物理静电模型能构建直观、形象的数学模型, 大大简化了计算量,因此能计算接近实际LDHs尺寸的体系, 为推测LDHs结构信息提供了可能性. 随着理论方法和计算机硬件水平的发展, 使得计算机模拟技术逐渐成为获得LDHs材料微观结构参数、电子性质和动力学性质的一种有效手段.     

Energetics of Zn2+ binding to a series of biologically relevant ligands: A molecular mechanics investigation grounded on ab initio self-consistent field supermolecular computations

Detailed investigations are performed of the binding energetics of Zn²⁺ to a series of neutral and anionic ligands making up the sidechains of amino acid residues of proteins, as well as ligands which can be involved in Zn²⁺ binding during enzymatic activation: imidazole, formamide, methanethiol, methanethiolate, methoxy, and hydroxy. The computations are performed using the SIBFA molecular mechanics procedure (SMM), which expresses the interaction energy under the form of four separate contributions related to the corresponding ab initio supermolecular ones: electrostatic, short-range repulsion, polarization, and charge transfer. Recent refinements to this procedure are first exposed. To test the reliability of this procedure in large-scale simulations of inhibitor binding to metalloenzyme cavities, we undertake systematic comparisons of the SMM results with those of recent large basis set ab initio self-consistent field (SCF) supermolecule computations, in which a decomposition of the total ΔE into its four corresponding components is done (N. Gresh, W. Stevens, and M. Krauss, J. Comp. Chem., 16 , 843, 1995). For each complex, the evolution of each individual SMM energy component as a function of radial and in- and out-of-plane angular variations of the Zn²⁺ position reproduces with good accuracy the behavior of the corresponding SCF term. Computations performed subsequently on di- and oligoligated complexes of Zn²⁺ show that the SIBFA molecular mechanics (SMM) functionals, E_pol and E_ct, closely account for the nonadditive behaviors of the corresponding second-order energy contributions determined from the ab initio SCF calculations on these complexes and their nonlinear dependence on the number of ligands. Thus, the total intermolecular interaction energies computed with this procedure reproduce, with good accuracy, the corresponding SCF ones without the need for additional, extraneous terms in the intermolecular potential of polyligated complexes of divalent cations. © 1995 by John Wiley & Sons, Inc.     

Comparative binding energetics of Mg2+, Ca2+, Zn2+, and Cd2+ to biologically relevant ligands: Combined ab initio SCF supermolecule and molecular mechanics investigation

A combined ab initio SCF supermolecule and molecular mechanics investigation is carried out on the binding energetics of the divalent cations Mg²⁺, Ca²⁺, Zn²⁺, and Cd²⁺ to a series of the most common ligand functional groups found in biomolecules. The SCF binding energy components are resolved using the restricted variational space method.¹ The results show that the SIBFA molecular mechanics (SMM) procedure² reproduces the ab initio binding energies and total energy variations as a function of intermolecular variables. The model also reproduces the selectivity energetics for exchange reactions. Thus, the SMM procedure can be used without reparametrization to describe the coordination energetics of complex molecules including those subject to coordination changes. The energetic properties of divalent cation-hexahydrate complexes are compared as examples of a complete, realistic coordination system. The hexahydrates exhibit strong nonadditive effects typical of dication coordination. Nevertheless, these energetics are satisfactorily reproduced by the SMM procedure. © 1996 John Wiley & Sons, Inc.