Specific interactions and binding free energies between thermolysin and dipeptides: molecular simulations combined with ab initio molecular orbital and classical vibrational analysis

Thermolysin (TLN) is a metalloprotease widely used as a nonspecific protease for sequencing peptide and synthesizing many useful chemical compounds by the chemical industry. It was experimentally shown that the activity and functions of TLN are inhibited by the binding of many types of amino acid dipeptides. However, the binding mechanisms between TLN and dipeptides have not been clarified at the atomic and electronic levels. In this study, we investigated the binding mechanisms between TLN and four dipeptides. Specific interactions and binding free energies (BFEs) between TLN and the dipeptides were calculated using molecular simulations based on classical molecular dynamics and ab initio fragment molecular orbital (FMO) methods. The molecular systems were embedded in solvating water molecules during calculations. The calculated BFEs were qualitatively consistent with the trend of the experimentally observed inhibition of TLN activity by binding of the dipeptides. In addition, the specific interactions between the dipeptides and each amino acid residue of TLN or solvating water molecules were elucidated by the FMO calculations.     

Intra- and intermolecular interactions between cyclic-AMP receptor protein and DNA: ab initio fragment molecular orbital study

The ab initio fragment molecular orbital (FMO) calculations were performed for the cAMP receptor protein (CRP) complexed with a cAMP and DNA duplex to elucidate their sequence-specific binding and the stability of the DNA duplex, as determined by analysis of their inter- and intramolecular interactions. Calculations were performed with the AMBER94 force field and at the HF and MP2 levels with several basis sets. The interfragment interaction energies (IFIEs) were analyzed for interactions of CRP-cAMP with each base pair, DNA duplex with each amino acid residue, and each base pair with each residue. In addition, base-base interactions were analyzed including hydrogen bonding and stacking of DNA. In the interaction between DNA and CRP-cAMP, there was a significant charge transfer (CT) from the DNA to CRP, and this CT interaction played an important role as well as the electrostatic interactions. It is necessary to apply a quantum mechanical approach beyond the "classical" force-field approach to describe the sequence specificity. In the DNA intramolecular interaction, the dispersion interactions dominated the stabilization of the base-pair stacking interactions. Strong, attractive 1,2-stacking interactions and weak, repulsive 1,3-stacking interactions were observed. Comparison of the intramolecular interactions of free and complexed DNA revealed that the base-pairing interactions were stronger, and the stacking interactions were weaker, in the complexed structure. Therefore, the DNA duplex stability appears to change due to both the electrostatic and the CT interactions that take place under conditions of DNA-CRP binding.     

Roles of K151 and D180 in L‐2‐haloacid dehalogenase from Pseudomonas sp. YL: Analysis by molecular dynamics and ab initio fragment molecular orbital calculations

L ‐2‐haloacid dehalogenase (L ‐DEX) catalyzes the hydrolytic dehalogenation of L ‐2‐haloalkanoic acids to produce the corresponding D ‐2‐hydroxyalkanoic acids. This enzyme is expected to be applicable to the bioremediation of environments contaminated with halogenated organic compounds. We analyzed the reaction mechanism of L ‐DEX from Pseudomonas sp. YL (L ‐DEX YL) by using molecular modeling. The complexes of wild‐type L ‐DEX YL and its K151A and D180A mutants with its typical substrate, L ‐2‐chloropropionate, were constructed by docking simulation. Subsequently, molecular dynamics (MD) and ab initio fragment molecular orbital (FMO) calculations of the complexes were performed. The ab initio FMO method was applied at the MP2/6‐31G level to estimate interfragment interaction energies. K151 and D180, which are experimentally shown to be important for enzyme activity, interact particularly strongly with L ‐2‐chloropropionate, catalytic water, nucleophile (D10), and with each other. Our calculations suggest that K151 stabilizes substrate orientation and balances the charge around the active site, while D180 stabilizes the rotation of the nucleophile D10, fixes catalytic water around D10, and prevents K151 from approaching D10. Further, D180 may activate catalytic water on its own or with K151, S175, and N177. These roles are consistent with the previous results. Thus, MD and ab initio FMO calculations are powerful tools for the elucidation of the mechanism of enzymatic reaction at the molecular level and can be applied to other catalytically important residues. The results obtained here will play an important role in elucidating the reaction mechanism and rational design of L ‐DEX YL with improved enzymatic activity or substrate specificity. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2009     

Protein‐specific force field derived from the fragment molecular orbital method can improve protein–ligand binding interactions

Accurate computational estimate of the protein–ligand binding affinity is of central importance in rational drug design. To improve accuracy of the molecular mechanics (MM) force field (FF) for protein–ligand simulations, we use a protein‐specific FF derived by the fragment molecular orbital (FMO) method and by the restrained electrostatic potential (RESP) method. Applying this FMO‐RESP method to two proteins, dodecin, and lysozyme, we found that protein‐specific partial charges tend to differ more significantly from the standard AMBER charges for isolated charged atoms. We did not see the dependence of partial charges on the secondary structure. Computing the binding affinities of dodecin with five ligands by MM PBSA protocol with the FMO‐RESP charge set as well as with the standard AMBER charges, we found that the former gives better correlation with experimental affinities than the latter. While, for lysozyme with five ligands, both charge sets gave similar and relatively accurate estimates of binding affinities. © 2013 Wiley Periodicals, Inc.     

Exceptional thermodynamic stability of DNA duplexes modified by nonpolar base analogues is due to increased stacking interactions and favorable solvation: Correlated ab initio calculations and molecular dynamics simulations

The geometries of DNA hexamer (5'-GGAACC-3') and DNA 13-mer (5'-GCGTACACATGCG-3') have been determined by molecular dynamics (MD) simulations using an empirical force field. The central canonical base pair was replaced by a pair of nonpolar base analogues, 2,2'-bipyridyl and 3-methylisocarbostyril. The stabilization energy of the model system (model A) consisting of a central base pair (base-analogue pair) and two neighboring base pairs was determined by the RI-MP2 method using an extended aug-cc-pVDZ basis set. The geometry of the model was averaged from structures determined by MD simulations. The role of the solvent was covered by the COSMO continuum solvent model and calculations were performed for a larger model system (model B) which also contained a sugar-phosphate backbone. The total stabilization energies of the unperturbed system and the system perturbed by a base-analogue pair (model A) were comparable to the stability of both duplexes experimentally determined. This is due to large stacking interaction energy of the base-analogue self-pair which compensates for the missing hydrogen-bonding energy of the replaced adenine...thymine base pair. The selectivity of the base-analogue pair was reproduced (model B) when their desolvation energy was included with the interaction energy of both strands determined by the approximate SCC-DFTB-D method.     

CH/pi hydrogen bonds determine the selectivity of the Src homology 2 domain to tyrosine phosphotyrosyl peptides: an ab initio fragment molecular orbital study

The CH/pi hydrogen bond is a weak molecular force occurring between CH groups (soft acids) and pi-systems (soft bases), and has been recognized to be important in the interaction of proteins with their specific ligands. For instance, it is well known that Src homology-2 protein (SH2) recognizes its specific pTyr peptide in two key regions, pTyr-binding region and specificity-determining region, by the use of attractive molecular forces, including the CH/pi hydrogen bond. We hypothesized that the CH/pi hydrogen bond plays a key role in determining the selectivity of SH2 proteins, and studied this issue by the ab initio fragment molecular orbital (FMO) method. The FMO calculations were carried out, at the HF/6-31G* and MP2/6-31G* level, for SH2 domains of Src, Grb2, P85alpha(N), Syk, and SAP, in complex with corresponding pTyr peptides. CH/pi hydrogen bonds have in fact been found to be important in stabilizing the structure of the complexes. We conclude that the CH/pi hydrogen bond plays an indispensable role in the recognition of SH2 domains with their specific pTyr peptides, thus playing a vital role in the signal transduction system.     

IMiCMO: a new integrated ab initio multicenter molecular orbitals method for molecular dynamics calculations in solvent cluster systems

A new computational scheme integrating ab initio multicenter molecular orbitals for determining forces of individual atoms in large cluster systems is presented. This method can be used to treat systems of many molecules, such as solvents by quantum mechanics. The geometry parameters obtained for three models of water clusters by the present method are compared with those obtained by the full ab initio MO method. The results agree very well. The scheme proposed in this article also intended for use in modeling cluster systems using parallel algorithms. © 2001 John Wiley & Sons, Inc. J Comput Chem 22: 1107–1112, 2001     

A further study on closo boron hydrides B16H2−16 (D2) and B16H16Td) using ab initio molecular orbital theory

Ab initio molecular orbital calculations of doubly negative charged B₁₆H^2?₁₆(D₂) and neutral B₁₆H₁₆(Td) have been done at the HF/6-31G level. They are predicted to be chemically and kinetically stable by vibrational analyses on their respective energy hypersurface of the HF/6-31G level. The geometrical structure of the species B₁₆H²₁₆ (D₂) was discussed.     

Studies on molecular interactions of β-cyclodextrin and antiulcer agent

The search for the lowest energy conformation of complex {β-cyclodextrin (β-CD)+chlorambucil} were carried out by molecular mechanics method. Theoretical calculations of molecular interactions of complex were carried out using the molecular orbital method. The correlation between energy changes and molecular structures are discussed. The large interaction energies calculated by the molecular orbital method bears out the inclusion phenomenon.     

DNA base trimers: empirical and quantum chemical ab initio calculations versus experiment in vacuo

A complete scan of the potential‐energy surfaces for selected DNA base trimers has been performed by a molecular dynamics/quenching technique using the force field of Cornell et al. implemented in the AMBER7 program. The resulting most stable/populated structures were then reoptimized at a correlated ab initio level by employing resolution of the identity, Møller–Plesset second‐order perturbation theory (RI‐MP2). A systematic study of these trimers at such a complete level of electronic structure theory is presented for the first time. We show that prior experimental and theoretical interpretations were incorrect in assuming that the most stable structures of the methylated trimers corresponded to planar systems characterized by cyclic intermolecular hydrogen bonding. We found that stacked structures of two bases with the third base in a T‐shape arrangement are the global minima in all of the methylated systems: they are more stable than the cyclic planar structures by about 10 kcal mol^?1. The different behaviors of nonmethylated and methylated trimers is also discussed. The high‐level geometries and interaction energies computed for the trimers serve also as a reference for the testing of recently developed density functional theory (DFT) functionals with respect to their ability to correctly describe the balance between the electrostatic and dispersion contributions that bind these trimers together. The recently reported M052X functional with a polarized triple‐zeta basis set predicts 11 uracil trimer interaction energies with a root‐mean‐square error of 2.3 kcal mol^?1 relative to highly correlated ab initio theoretical calculations.     

Assessment and acceleration of binding energy calculations for protein–ligand complexes by the fragment molecular orbital method

In the field of drug discovery, it is important to accurately predict the binding affinities between target proteins and drug applicant molecules. Many of the computational methods available for evaluating binding affinities have adopted molecular mechanics‐based force fields, although they cannot fully describe protein–ligand interactions. A noteworthy computational method in development involves large‐scale electronic structure calculations. Fragment molecular orbital (FMO) method, which is one of such large‐scale calculation techniques, is applied in this study for calculating the binding energies between proteins and ligands. By testing the effects of specific FMO calculation conditions (including fragmentation size, basis sets, electron correlation, exchange‐correlation functionals, and solvation effects) on the binding energies of the FK506‐binding protein and 10 ligand complex molecule, we have found that the standard FMO calculation condition, FMO2‐MP2/6‐31G(d), is suitable for evaluating the protein–ligand interactions. The correlation coefficient between the binding energies calculated with this FMO calculation condition and experimental values is determined to be R = 0.77. Based on these results, we also propose a practical scheme for predicting binding affinities by combining the FMO method with the quantitative structure–activity relationship (QSAR) model. The results of this combined method can be directly compared with experimental binding affinities. The FMO and QSAR combined scheme shows a higher correlation with experimental data (R = 0.91). Furthermore, we propose an acceleration scheme for the binding energy calculations using a multilayer FMO method focusing on the protein–ligand interaction distance. Our acceleration scheme, which uses FMO2‐HF/STO‐3G:MP2/6‐31G(d) at R_int = 7.0 Å, reduces computational costs, while maintaining accuracy in the evaluation of binding energy. © 2015 Wiley Periodicals, Inc.     

A further study on closo boron hydrides B_(16)H_(16)~(2-)(D_2) and B_(16)H_(16)(Td) using ab initio molecular orbital theory

Ab initio molecular orbital calculations of doubly negative charged B16H162-(D2) and neutral B16H16(Td) have been done at the HF/6-31G level.They are predicted to be chemically and kinetically stable by vibrational analyses on their respective energy hypersurface of the HF/6-31G level.The geometrical structure of the species B16H1622-(D2) was discussed.     

Spectroscopic properties in the liquid phase: combining high-level ab initio calculations and classical molecular dynamics.

We present an integrated computational tool, rooted in density functional theory, the polarizable continuum model, and classical molecular dynamics employing spherical boundary conditions, to study the spectroscopic observables of molecules in solution. As a test case, a modified OPLS-AA force field has been developed and used to compute the UV and NMR spectra of acetone in aqueous solution. The results show that provided the classical force fields are carefully reparameterized and validated, the proposed approach is robust and effective, and can also be used by nonspecialists to provide a general and powerful complement to experimental techniques.     

Molecular structure of aniline in the gaseous phase: A concerted study by electron diffraction and ab initio molecular orbital calculations

The molecular structure of free aniline has been investigated by gas-phase electron diffraction and ab initio MO calculations at the HF and MP2 levels of theory, using the 6-31G^*(6D) basis set. Least-squares refinement of a model withC _s symmetry, with constraints from MP2 calculations, has led to an accurate determination of the C-C-C angle at theipso position of the benzene ring, =119.0±0.2 (where the uncertainty represents total error). This parameter provides information on the extent of the interaction between the nitrogen lone pair and the system of the benzene ring, and could not be determined accurately by microwave spectroscopy. The angles at theortho, meta, andpara positions of the ring are 120.3±0.1, 120.7±0.1, and 119.0±0.3, respectively. Important bond distances are r _g(C-C)=1.398±0.003 å andr _g(C-N) =1.407±0.003 å. The effective dihedral angle between the H-N-H plane and the ring plane, averaged over the large-amplitude inversion motion of the amino group, is ¦¦=44±4. The equilibrium dihedral angle is calculated to be 41.8 at the HF level and 43.6 at the MP2 level, in agreement with far-infrared spectroscopic information. The MO calculations predict that the differencer(C_ortho-C_meta) -r(C_ipso-C_ortho) is 0.008–0.009 å. They also indicate that the nitrogen atom is displaced from the ring plane, on the side opposite to the amino hydrogens. The displacement is 0.049 å at the HF level and 0.072 å at the MP2 level. The two calculations, however, yield very different patterns for the minute deviations from planarity of the ring carbons.     

Organolithium complex as a gas sensing material for oxides from ab initio calculations and molecular dynamics simulations

Gas sensing study of C₂H₄Li complex toward oxides viz. CO, CO₂, NO, NO₂, SO, and SO₂ gas molecules has been carried out using ab initio method. Different possible configurations of gas molecule adsorption on C₂H₄Li complex are considered. The structural parameters of most stable configuration of gas molecule adsorbed complexes are thoroughly analysed. Electronic properties are studied using total density of states (DOS) plot. Charge transferred between the gas molecule and the substrate is studied using NBO charge analysis. Gas sensing of all the six gas molecules is possible at ambient conditions. Atom centred density matrix propagation (ADMP) molecular dynamics simulations confirmed that all the gas molecules remain adsorbed on C₂H₄Li complex at room temperature during the simulation. This study suggests that the C₂H₄Li complex acts as a novel gas sensing material for CO, CO₂, NO, NO₂, SO, and SO₂ gas molecules at ambient conditions, below room temperature as well as at high pressure.     

Semi-empirical (PM3 and AM1) and ab initio molecular orbital calculations of 1,2,4-oxadiazoles, 4,5-dihydro-1,2,4-oxadiazoles and 4,4-di-n-butyl-2-phenylbenzo-1,3-oxazine

Molecular orbital calculations using semi-empirical (PM3 and AM1) and ab initio (HF/6-31G) types have been carried out on several 3,5-disubstituted 1,2,4-oxadiazoles 1a–d, 5-n-butyl-3,5-diaryl-4,5-dihydro-1,2,4-oxadiazoles 2a–d, and 4,4-di-n-butyl-2-phenylbenzo-1,3-oxazine 3. A comparison of the results by the two computational procedures has been made. Transformation of the oxadiazole ring to 4,5-dihydro-1,2,4-oxadiazole having both aryl and n-butyl groups at C-5 exhibited interesting conformational features. Also, examination of 1,3-oxazine 3 gave an idea about the structure of this compound. The rotational barrier of each phenyl group in 1a and 1d has been calculated using the ab initio method HF/6-31G(d).     

Ab initio quantum mechanical study of the binding energies of human estrogen receptor alpha with its ligands: an application of fragment molecular orbital method

We have theoretically examined the relative binding affinities (RBA) of typical ligands, 17beta-estradiol (EST), 17alpha-estradiol (ESTA), genistein (GEN), raloxifene (RAL), 4-hydroxytamoxifen (OHT), tamoxifen (TAM), clomifene (CLO), 4-hydroxyclomifene (OHC), diethylstilbestrol (DES), bisphenol A (BISA), and bisphenol F (BISF), to the alpha-subtype of the human estrogen receptor ligand-binding domain (hERalpha LBD), by calculating their binding energies. The ab initio fragment molecular orbital (FMO) method, which we have recently proposed for the calculations of macromolecules such as proteins, was applied at the HF/STO-3G level. The receptor protein was primarily modeled by 50 amino acid residues surrounding the ligand. The number of atoms in these model complexes is about 850, including hydrogen atoms. For the complexes with EST, RAL, OHT, and DES, the binding energies were calculated again with the entire ERalphaLBD consisting of 241 residues or about 4000 atoms. No significant difference was found in the calculated binding energies between the model and the real protein complexes. This indicates that the binding between the protein and its ligands is well characterized by the model protein with the 50 residues. The calculated binding energies relative to EST were very well correlated with the experimental RBA (the correlation coefficient r=0.837) for the ligands studied in this work. We also found that the charge transfer between ER and ligands is significant on ER-ligand binding. To our knowledge, this is the first achievement of ab initio quantum mechanical calculations of large molecules such as the entire ERalphaLBD protein.     

Polymerization of coordinated monomers. XXI. Ab initio molecular orbital study on the binary molecular complex composed of methyl methacrylate and boron trifluoride

The stereo- and electronic structures of the binary molecular complex composed of methyl methacrylate and boron trifluoride are obtained by using an ab initio molecular orbital method with an STO-3G basis set. The total energy change on the binary molecular complex formation is ?1.3 X 10^?2 Hartree (?8.2 kcal/mol). The electron transfer from methyl methacrylate to boron trifluoride and the change in the energy level of the lowest unoccupied molecular orbital of methyl methacrylate on the complex formation with boron trifluoride are much smaller than those on the complex formation with boron trichloride. A twisted form in which the dihedral angle between the vinyl plane and the ester plane is 16.9° is the most stable structure of the binary molecular complex composed of methyl methacrylate and boron trifluoride. A strong bonding overlap population between a β-hydrogen of methyl methacrylate and a fluorine of boron trifluoride is found in this conformation. © 1992 John Wiley & Sons, Inc.     

Molecular structure and vibrational spectra of phenobaraitone by density functional theory and ab initio hartree-Fock calculations

Quantum chemistry calculations have been performed using Gaussian03 program to compute optimized geometry, harmonic vibrational frequency along with intensities in IR and Raman spectra at RHF/6-31++G** and B3LYP/6-31++G** levels for phenobarbitone (C₁₂H₁₂N₂O₃) in the ground state. The scaled harmonic vibrational frequencies have been compared with experimental FT-IR and FT-Raman spectra. Theoretical vibrational spectra of the title compound were interpreted by means of potential energy distributions (PEDs) using MOLVIB program. A detailed interpretation of the infrared spectra of the title compound is reported. On the basis of the agreement between the calculated and observed results, the assignments of fundamental vibrational modes of phenobarbitone were examined and some assignments were proposed. The theoretical spectrograms for FT-IR and FT-Raman spectra of the title compound have been constructed.