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 Ec. For all three halogenated compounds, and with both probes, the in‐ and out‐of‐plane angular features of Ec were closely mirrored by the SIBFA electrostatic multipolar contribution (EMTP). 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.

[1]  Nohad Gresh,et al.  Polarizable water molecules in ligand-macromolecule recognition. Impact on the relative affinities of competing pyrrolopyrimidine inhibitors for FAK kinase. , 2010, Journal of the American Chemical Society.

[2]  Stefan Güssregen,et al.  Evidence for C-Cl/C-Br...pi interactions as an important contribution to protein-ligand binding affinity. , 2009, Angewandte Chemie.

[3]  Pavel Hobza,et al.  Strength and Character of Halogen Bonds in Protein–Ligand Complexes , 2011 .

[4]  Peter Politzer,et al.  Expansion of the σ-hole concept , 2009, Journal of molecular modeling.

[5]  Pavel Hobza,et al.  Investigations into the Nature of Halogen Bonding Including Symmetry Adapted Perturbation Theory Analyses. , 2008, Journal of chemical theory and computation.

[6]  Pavel Hobza,et al.  Br···O Complexes as Probes of Factors Affecting Halogen Bonding: Interactions of Bromobenzenes and Bromopyrimidines with Acetone. , 2009, Journal of chemical theory and computation.

[7]  Pierangelo Metrangolo,et al.  Halogen bonding based recognition processes: a world parallel to hydrogen bonding. , 2005, Accounts of chemical research.

[8]  Célia Fonseca Guerra,et al.  The Nature of the Hydrogen Bond in DNA Base Pairs: The Role of Charge Transfer and Resonance Assistance , 1999 .

[9]  Frank H. Allen,et al.  The Nature and Geometry of Intermolecular Interactions between Halogens and Oxygen or Nitrogen , 1996 .

[10]  François Diederich,et al.  Systematic investigation of halogen bonding in protein-ligand interactions. , 2011, Angewandte Chemie.

[11]  Marcelo Zaldini Hernandes,et al.  Halogen atoms in the modern medicinal chemistry: hints for the drug design. , 2010, Current drug targets.

[12]  P. Claverie,et al.  Computations of intermolecular interactions: Expansion of a charge-transfer energy contribution in the framework of an additive procedure. Applications to hydrogen-bonded systems , 1982 .

[13]  Weiliang Zhu,et al.  Halogen bonding--a novel interaction for rational drug design? , 2009, Journal of medicinal chemistry.

[14]  Nohad Gresh,et al.  Polarizable water networks in ligand-metalloprotein recognition. Impact on the relative complexation energies of Zn-dependent phosphomannose isomerase with D-mannose 6-phosphate surrogates. , 2011, The journal of physical chemistry. B.

[15]  Mark S. Gordon,et al.  General atomic and molecular electronic structure system , 1993, J. Comput. Chem..

[16]  Nohad Gresh,et al.  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 , 2007, J. Comput. Chem..

[17]  Nohad Gresh,et al.  Energetics of Zn2+ binding to a series of biologically relevant ligands: A molecular mechanics investigation grounded on ab initio self‐consistent field supermolecular computations , 1995, J. Comput. Chem..

[18]  Jean-Philip Piquemal,et al.  A CSOV study of the difference between HF and DFT intermolecular interaction energy values: The importance of the charge transfer contribution , 2005, J. Comput. Chem..

[19]  Anthony J. Stone,et al.  Distributed multipole analysis, or how to describe a molecular charge distribution , 1981 .

[20]  T. H. Dunning Gaussian basis sets for use in correlated molecular calculations. I. The atoms boron through neon and hydrogen , 1989 .

[21]  Nohad Gresh,et al.  Complexes of thiomandelate and captopril mercaptocarboxylate inhibitors to metallo‐β‐lactamase by polarizable molecular mechanics. Validation on model binding sites by quantum chemistry , 2005, J. Comput. Chem..

[22]  Pavel Hobza,et al.  Advanced Corrections of Hydrogen Bonding and Dispersion for Semiempirical Quantum Mechanical Methods. , 2012, Journal of chemical theory and computation.

[23]  Mahmoud A. A. Ibrahim,et al.  Molecular mechanical study of halogen bonding in drug discovery , 2011, J. Comput. Chem..

[24]  Jean-Philip Piquemal,et al.  NCIPLOT: a program for plotting non-covalent interaction regions. , 2011, Journal of chemical theory and computation.

[25]  Pavel Hobza,et al.  On Extension of the Current Biomolecular Empirical Force Field for the Description of Halogen Bonds. , 2012, Journal of chemical theory and computation.

[26]  Timothy Clark,et al.  Halogen bonding: an electrostatically-driven highly directional noncovalent interaction. , 2010, Physical chemistry chemical physics : PCCP.

[27]  David Feller The role of databases in support of computational chemistry calculations , 1996 .

[28]  Jun Li,et al.  Basis Set Exchange: A Community Database for Computational Sciences , 2007, J. Chem. Inf. Model..

[29]  Julia Contreras-García,et al.  Revealing noncovalent interactions. , 2010, Journal of the American Chemical Society.

[30]  Eric Westhof,et al.  Halogen bonds in biological molecules. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[31]  Marcin Palusiak,et al.  On the nature of halogen bond – The Kohn–Sham molecular orbital approach , 2010 .

[32]  W. J. Stevens,et al.  Transferability of molecular distributed polarizabilities from a simple localized orbital based method , 1989 .

[33]  S. Durell,et al.  Specificity of acyl transfer from 2-mercaptobenzamide thioesters to the HIV-1 nucleocapsid protein. , 2007, Journal of the American Chemical Society.

[34]  Nohad Gresh,et al.  Development, validation, and applications of anisotropic polarizable molecular mechanics to study ligand and drug-receptor interactions. , 2006, Current pharmaceutical design.

[35]  S. Papson “Model” , 1981 .

[36]  Nohad Gresh,et al.  Anisotropic, Polarizable Molecular Mechanics Studies of Inter- and Intramolecular Interactions and Ligand-Macromolecule Complexes. A Bottom-Up Strategy. , 2007, Journal of chemical theory and computation.

[37]  P. Claverie,et al.  The exact multicenter multipolar part of a molecular charge distribution and its simplified representations , 1988 .

[38]  M. Alderton,et al.  Distributed multipole analysis , 2006 .

[39]  J. G. Snijders,et al.  Hydrogen Bonding in DNA Base Pairs: Reconciliation of Theory and Experiment , 2000 .

[40]  Pierangelo Metrangolo,et al.  Halogen bonding in supramolecular chemistry. , 2008, Angewandte Chemie.

[41]  Timothy Clark,et al.  Polarization-induced σ-holes and hydrogen bonding , 2012, Journal of Molecular Modeling.

[42]  JENS ANTONY,et al.  Binding of D‐ and L‐captopril inhibitors to metallo‐β‐lactamase studied by polarizable molecular mechanics and quantum mechanics , 2002, J. Comput. Chem..

[43]  Stefan Grimme,et al.  Semiempirical GGA‐type density functional constructed with a long‐range dispersion correction , 2006, J. Comput. Chem..

[44]  William H. Fink,et al.  Frozen fragment reduced variational space analysis of hydrogen bonding interactions. Application to the water dimer , 1987 .

[45]  Timothy Clark,et al.  Halogen bonding: the σ-hole , 2007 .