Binding of D- and L-captopril inhibitors to metallo-beta-lactamase studied by polarizable molecular mechanics and quantum mechanics

The bacterial Zn2+ metallo-beta-lactamase from B. fragilis is a zinc-enzyme with two potential metal ion binding sites. It cleaves the lactam ring of antibiotics, thus contributing to the acquired resistance of bacteria against antibiotics. The present study bears on the binuclear form of the enzyme. We compare several possible binding modes of captopril, a mercaptocarboxamide inhibitor of several zinc-metalloenzymes. Two diastereoisomers of captopril were considered, with either a D- or an L-proline residue. We have used the polarizable molecular mechanics procedure SIBFA (Sum of Interactions Between Fragments ab initio computed). Two beta-lactamase models were considered, encompassing 104 and 188 residues, respectively. The energy balances included the inter and intramolecular interaction energies as well as the contribution from solvation computed using a continuum reaction field procedure. The thiolate ion of the inhibitor is binding to both metal ions, expelling the bridging solvent molecule from the uncomplexed enzyme. Different competing binding modes of captopril were considered, either where the inhibitor binds in a monodentate mode to the zinc cations only with its thiolate ion, or in bidentate modes involving additional zinc binding by its carboxylate or ketone carbonyl groups. The additional coordination by the inhibitor's carboxylate or carbonyl group always occurs at the zinc ion, which is bound by a histidine, a cysteine, and an aspartate side chain. For both diastereomers, the energy balances favor monodentate binding of captopril via S-. The preference over bidentate binding is small. The interaction energies were recomputed in model sites restricted to captopril, the Zn2+ cations, and their coordinating end side chains from beta-lactamase (98 atoms). The interaction energies and their ranking among competing arrangements were consistent with those computed by ab initio HF and DFT procedures.     

A supermolecule study of the effect of hydration on the conformational behaviour of leucine-enkephalin

Summary A theoretical conformational study was performed on leu-enkephalin in its zwitterionic form, both in vacuo and in the presence of a number, n, of up to 13 water molecules saturating its first hydration shell. The intramolecular energy of enkephalin as well as the intermolecular enkephalin-water and water-water interaction energies were computed with the SIBFA procedure (Sum of Interactions Between Fragments Ab initio computed), which uses additive ab initio multipole systematics and analytical formulas grounded on ab initio SCF computations. Energy minimizations were performed with a polyvalent minimizer, Merlin, with which three distinct derivative and three distinct nonderivative minimizers can be activated in a sequential fashion.Eight different candidate conformations of enkephalin were used as starting points. These conformations are either those found in distinct X-ray structures, or those proposed on the basis of theoretical computations by other authors. In the absence of hydration, they converged towards distinct folded energy-minima, the best four ones being separated by an energy gap of 8.7 kcal/mol. In marked contrast, with up to n=13, the energetical separation between the six best conformers narrowed down to 4 kcal/mol. They can be characterized by: (a) either a direct or a water-mediated ammonium-carboxylate interaction; b) either a close proximity (as in morphine) or a large separation between the aromatic rings of Tyr and Phe (intercenter separations of 4.5 Å and 10.5 Å, respectively), with each of the four mutual combinations of (a) and (b) being represented.     

A theoretical study of the interaction of monomethylammonium with double-stranded oligonucleotides

Theoretical computations are performed of the interaction specificities of the monomethylammoniumion with double-stranded oligonucleotides (dPu)_n·(dPy)_n in the B-DNA conformation. The effects of base sequence and chain length are examined. In short oligomers (n = 2, 3), the interaction energies of the cation are larger in the major groove of (dG)_n·(dC)_n than in the minor groove of (dA)_n·(dT)_n. As a consequence of further shaping of the grooves and building up of the phosphates, a marked reversal in the affinities of the cation for the grooves occurs at the (dPu)₅·(dPy)₅ and the p(dPu)₅p·p(dPy)₅p levels: it is the binding in the minor groove of the adenine-thymine oligomers that provides then the most favorable interaction energies. It is also shown, at the level of the double helices built from dinucleoside monophosphates, that the interaction of monomethylammonium in the minor groove occurs in specific configurations involving the three NH bonds of the cation, and two successive bases on one strand; this binding is sequence-specific, the order of inherent preferences being (TpA) > (TpT) > (ApA) > (ApT).     

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.     

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.     

Key role of the polarization anisotropy of water in modeling classical polarizable force fields

We have evaluated the extent to which classical polarizable force fields, based either on the chemical potential equalization principle or on distributed polarizabilities in the framework of the Sum of Interactions Between Fragments Ab initio computed (SIBFA), can reproduce the ab initio polarization energy and the dipole moment of three distinct water oligomers: bifurcated chains, transverse hydrogen-bonded chains, and longitudinal hydrogen-bonded chains of helical shape. To analyze the many-body polarization effect, chains of different size, i.e., from 2 to 12 water monomers, have been considered. Although the dipole moment is a well-defined quantity in both classical polarizable models and quantum mechanical methods, polarization energy can be defined unequivocally only in the former type of approaches. In this study we have used the Kitaura-Morokuma (KM) procedure. Although the KM approach is on the one hand known to overestimate the polarization energy for strongly interacting molecules, on the other hand it can account for the many-body polarization effectively, whereas some other procedures do not. Our data show that, if off-centered lone pair polarizabilities are explicitly represented, classical polarizable force fields can afford a close agreement with the ab initio results, both in terms of polarization energy and in terms of dipole moment.     

Could the “Janus‐like” properties of the halobenzene CX bond (XCl,Br) be leveraged to enhance molecular recognition?

The CX bond in halobenzenes (X?Cl, Br) exhibits a dual character, being electron‐deficient along the CX direction, and electron‐rich on its flanks. We sought to amplify both features by resorting to electron‐withdrawing and electron‐donating substituents, respectively. This was done by quantum chemistry (QC) computations in the recognition sites of three protein targets: farnesyl transferase, coagulation factor Xa, and the HIV‐1 integrase. In this context, some substituents, notably fluorine, CF₃, and NHCH₃, afforded significant overall gains in the binding energies as compared to the parent halobenzene, in the 2–5 kcal/mol range. In fact, we found that some di‐ and up to tetra‐substitutions enabled even larger gains than those they contribute separately owing to many‐body effects. Moreover, desolvation was also found to be a key contributor to the energy balances. As a consequence, some particular substituents, contributing to reduce the halobenzene dipole moment, accordingly reduced solvation: this factor acted in synergy with their enhancement of the intermolecular interaction energies along and around the CX bond. We could thus leverage the “Janus‐like” properties of such a bond and the fact that it can be tuned and possibly amplified by well‐chosen substituents. We propose a simple yet rigorous computational strategy resorting to QC to prescreen novel substituted halobenzenes. The QC results on the recognition sites then set benchmarks to validate polarizable molecular mechanics/dynamics approaches used to handle the entirety of the inhibitor‐protein complex. © 2014 Wiley Periodicals, Inc.     

Joint quantum chemical and polarizable molecular mechanics investigation of formate complexes with penta- and hexahydrated Zn2+: Comparison between energetics of model bidentate,monodentate, and through-water Zn2+ binding modes and evaluation of nonadditivity effects

In order to gain an understanding of the energetics of polycoordinated Zn²⁺ binding to the formate anion (the end side chain of the Asp and Glu residues of proteins), we compare three competing binding modes in the presence of five and six water molecules: a, bidentate binding of Zn²⁺ to both formate oxygens; b, monodentate binding of Zn²⁺ to one formate oxygen; and c, through-water binding of Zn²⁺ to formate, in which the cation remains bound to its first-hydration shell waters and interacts with both formate oxygens through three water molecules. We also investigate a complex d, which is similar to c, in which formate is protonated into formic acid and one water molecule is deprotonated. The computations are carried out using the ab initio self-consistent field/MP2 with three basis sets of increasing size density functional theory, semiempirical AM1 and PM3, and the sum of interactions between fragments ab initio computed (SIBFA) molecular mechanics procedures. The summed energies of the isolated molecules making up the complexes disfavor tautomer d compared to a–c. On the other hand, the ab initio computations give the ordering of intermolecular interaction energies as d formic acid tautomer >b monodentate >a bidentate >c through-water. Whereas the first-order energy E₁ favors both inner-shell Zn²⁺ complexes with formate over the outer-shell complex, the polarization and the charge-transfer components of the second-order energy E₂ both favor the outer-shell complex over the inner-shell one, despite the increased separation between the cation and the highly polarizable formate ion. Energy balances including continuum solvation enthalpies produce an equilibration of complexes a–d. The preference favoring the monodentate complex over the bidentate one is consistent with other ab initio results for formate binding by a fully coordinated Zn²⁺ cation and with structural results from X-ray crystallography. The SIBFA results are consistent with the ab initio results, and the computed interaction energy values match the ab initio ones to within 3%. The effects of nonadditivity are analyzed in the ab initio, SIBFA, and semiempirical computations. ©1999 John Wiley & Sons, Inc. J Comput Chem 20: 1379–1390, 1999     

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.     

Intramolecular chelation of Zn2+ by α‐ and β‐mercaptocarboxamides. A parallel ab initio and polarizable molecular mechanics investigation. Assessment of the role of multipole transferability

α‐ and β‐mercaptocarboxamides constitute the Zn²⁺‐ligating entity of several highly potent metalloenzyme inhibitors. We have studied their interaction energies with Zn²⁺ using the polarizable molecular mechanics procedure SIBFA, and compared them to the corresponding ab initio supermolecule ones. Such validations are necessary to subsequently undertake simulations on complexes of Zn²⁺–metalloenzymes with inhibitors. If the distributed multipoles and polarizabilities are those derived for each ligand in its appropriate Zn²⁺‐binding conformation, a close reproduction of the ab initio binding energies is afforded. However, this representation is not tractable upon increasing the size of the ligands and/or to explore a continuum of binding conformations. This makes it necessary to construct the ligands by resorting to a library of constitutive fragments, namely in this case methanethiolate, formamide, and methane covalently connected together. A close reproduction of the ab initio interaction energies is enabled, but only if the ligand–ligand interactions are computed simultaneously with those occurring with Zn²⁺. This representation accounts for the nonadditivity occurring in the Zn²⁺–methanethiolate–formamide complex, and justifies the use of the distributed multipoles on the fragments for the construction of larger and flexible molecules. © 2001 John Wiley & Sons, Inc. J Comput Chem 22: 1038–1047, 2001