The first microsolvation step for furans: New experiments and benchmarking strategies.

The site-specific first microsolvation step of furan and some of its derivatives with methanol is explored to benchmark the ability of quantum-chemical methods to describe the structure, energetics, and vibrational spectrum at low temperature. Infrared and microwave spectra in supersonic jet expansions are used to quantify the docking preference and some relevant quantum states of the model complexes. Microwave spectroscopy strictly rules out in-plane docking of methanol as opposed to the top coordination of the aromatic ring. Contrasting comparison strategies, which emphasize either the experimental or the theoretical input, are explored. Within the harmonic approximation, only a few composite computational approaches are able to achieve a satisfactory performance. Deuteration experiments suggest that the harmonic treatment itself is largely justified for the zero-point energy, likely and by design due to the systematic cancellation of important anharmonic contributions between the docking variants. Therefore, discrepancies between experiment and theory for the isomer abundance are tentatively assigned to electronic structure deficiencies, but uncertainties remain on the nuclear dynamics side. Attempts to include anharmonic contributions indicate that for systems of this size, a uniform treatment of anharmonicity with systematically improved performance is not yet in sight.

Far-IR and UV spectral signatures of controlled complexation and microhydration of the polycyclic aromatic hydrocarbon acenaphthene.

In this work we report on the experimental and theoretical investigations of the progressional complexation of the polycyclic aromatic hydrocarbon (PAH) acenaphthene with itself and with water. In the interstellar medium, PAH complexes are an important link between molecular gas and solid state configurations of carbon, and in the form of grains they are postulated to serve as chemical catalysts. However, no direct detection of PAHs or their (microhydrated) complexes in interstellar space has been achieved as of yet. Therefore, we provide UV and far-infrared ion dip spectra of homogeneous PAH multimers and their hydrated clusters. The far-IR region of the IR spectrum is especially interesting since it contains the most spectral features that arise due to complexation or microhydration. We present microhydrated PAH complexes up to the third order, where we show that the water clusters are locked with little perturbation on the different PAH platforms. Density functional theory (DFT) calculations involving hydrogen bond interactions still seem challenging for predicting the far-IR frequency range, although applying anharmonic corrections leads to slight improvements.

The furan microsolvation blind challenge for quantum chemical methods: First steps.

Herein we present the results of a blind challenge to quantum chemical methods in the calculation of dimerization preferences in the low temperature gas phase. The target of study was the first step of the microsolvation of furan, 2-methylfuran and 2,5-dimethylfuran with methanol. The dimers were investigated through IR spectroscopy of a supersonic jet expansion. From the measured bands, it was possible to identify a persistent hydrogen bonding OH-O motif in the predominant species. From the presence of another band, which can be attributed to an OH-π interaction, we were able to assert that the energy gap between the two types of dimers should be less than or close to 1 kJ/mol across the series. These values served as a first evaluation ruler for the 12 entries featured in the challenge. A tentative stricter evaluation of the challenge results is also carried out, combining theoretical and experimental results in order to define a smaller error bar. The process was carried out in a double-blind fashion, with both theory and experimental groups unaware of the results on the other side, with the exception of the 2,5-dimethylfuran system which was featured in an earlier publication.

HYDROPHOBE Challenge: A Joint Experimental and Computational Study on the Host-Guest Binding of Hydrocarbons to Cucurbiturils, Allowing Explicit Evaluation of Guest Hydration Free-Energy Contributions.

The host-guest complexation of hydrocarbons (22 guest molecules) with cucurbit[7]uril was investigated in aqueous solution using the indicator displacement strategy. The binding constants (103-109 M-1) increased with guest size, pointing to the hydrophobic effect and dispersion interactions as driving forces. The measured affinities provide unique benchmark data for the binding of neutral guest molecules. Consequently, a computational blind challenge, the HYDROPHOBE challenge, was conducted to allow a comparison with state-of-the-art computational methods for predicting host-guest affinity constants. In total, three quantum-chemical (QM) data sets and two explicit-solvent molecular dynamics (MD) submissions were received. When searching for sources of uncertainty in predicting the host-guest affinities, the experimentally known hydration energies of the investigated hydrocarbons were used to test the employed solvation models (explicit solvent for MD and COSMO-RS for QM). Good correlations were obtained for both solvation models, but a rather constant offset was observed for the COSMO data, by ca. +2 kcal mol-1, which was traced back to a required reference-state correction in the QM submissions (2.38 kcal mol-1). Introduction of the reference-state correction improved the predictive power of the QM methods, particularly for small hydrocarbons up to C5.

Intramolecular London Dispersion Interaction Effects on Gas-Phase and Solid-State Structures of Diamondoid Dimers.

The covalent diamantyl (C28H38) and oxadiamantyl (C26H34O2) dimers are stabilized by London dispersion attractions between the dimer moieties. Their solid-state and gas-phase structures were studied using a multitechnique approach, including single-crystal X-ray diffraction (XRD), gas-phase electron diffraction (GED), a combined GED/microwave (MW) spectroscopy study, and quantum chemical calculations. The inclusion of medium-range electron correlation as well as the London dispersion energy in density functional theory is essential to reproduce the experimental geometries. The conformational dynamics computed for C26H34O2 agree well with solution NMR data and help in the assignment of the gas-phase MW data to individual diastereomers. Both in the solid state and the gas phase the central C-C bond is of similar length for the diamantyl [XRD, 1.642(2) Å; GED, 1.630(5) Å] and the oxadiamantyl dimers [XRD, 1.643(1) Å; GED, 1.632(9) Å; GED+MW, 1.632(5) Å], despite the presence of two oxygen atoms. Out of a larger series of quantum chemical computations, the best match with the experimental reference data is achieved with the PBEh-3c, PBE0-D3, PBE0, B3PW91-D3, and M06-2X approaches. This is the first gas-phase confirmation that the markedly elongated C-C bond is an intrinsic feature of the molecule and that crystal packing effects have only a minor influence.

Using dispersion-corrected density functional theory to understand supramolecular binding thermodynamics.

A recently published theoretical approach employing a nondynamic structure model using dispersion-corrected density functional theory (DFT-D3) to calculate equilibrium free energies of association (Chem. Eur. J., 2012, 18, 9955-9964) is illustrated by its application to eight new supramolecular complexes. We compare with experimentally known binding constants which span the range from -3.3 to -20.3 kcal mol(-1). The mean deviation of calculated from measured ΔGa results in 0.4 kcal mol(-1), the mean absolute deviation in 1.8 kcal mol(-1) excluding two outliers for which the computed solvation free energies are identified as the largest error source. A survey of previous applications of the theoretical approach and related computational studies is given underlining its good accuracy. It is concluded that structures and gas phase interaction energies can be computed routinely with good to high accuracy (relative errors for interaction energies of 5-10%) for complexes with about 200-300 atoms.

Blind prediction of binding affinities for charged supramolecular host-guest systems: achievements and shortcomings of DFT-D3.

Association free energies ΔGa are calculated for two different types of host-guest systems, the rigid cucurbit[7]uril (CB7) and the basket shaped octa-acid (OA), and a number of charged guest molecules each by quantum chemical methods from first principles in the context of a recent blind test challenge (SAMPL4). For CB7, the overall agreement between theory and experiment is excellent. In comparison with all other submitted calculated relative ΔGa,rel values for this part of the blind test, our results ranked on top. Modeling the binding free energy in the case of the OA host mainly suffers from the problem that the binding situation is undefined with respect to the charge state and due to its intrinsic flexibility the host-guest complex is not represented well by a single configuration, but qualitative features of the binding process such as the proper binding orientation and the order of magnitude of ΔGa are represented in accord with the experimental expectations even though an accurate ranking is not possible.

Theoretical study of the stacking behavior of selected polycondensed aromatic hydrocarbons with various symmetries.

Stacked dimers of four polycondensed aromatic hydrocarbons, with structures varying from high to reduced symmetries, have been calculated with dispersion-corrected density functional theory. The configurations of the stacked dimers are readily classified by two in-plane displacements and a relative rotation. The potential energy surface in these three coordinates was calculated with rigid monomers and appears to be slightly flat. Full geometry optimization was performed for selected low-energy structures, resulting in an energy ranking of a series of conformations whose geometries were characterized in considerable detail. The dissociation energy values reveal a clear preference for the symmetrical disk-shaped and triangular structures to dimerize into two in-plane-displaced arrangements, whereas the less symmetrical trapezoidal structures show a tendency to stack in displaced antiparallel over parallel arrangements. According to methodical checks, the key computational results, namely, the shape of the potential energy surface and the geometrical structures and energy ranking of dimer conformations, are essentially insensitive to computational assumptions such as the atomic orbital basis set and density functional chosen. This is shown in particular for the basis set superposition error, which, for the selected level of theory [B97-D3(BJ)/TZV(d,p)] was estimated by the counterpoise correction procedure to be in the narrow range between 7% and 8% of the uncorrected dissociation energies.

Fully ab initio protein-ligand interaction energies with dispersion corrected density functional theory.

Dispersion corrected density functional theory (DFT-D3) is used for fully ab initio protein-ligand (PL) interaction energy calculation via molecular fractionation with conjugated caps (MFCC) and applied to PL complexes from the PDB comprising 3680, 1798, and 1060 atoms. Molecular fragments with n amino acids instead of one in the original MFCC approach are considered, thereby allowing for estimating the three-body and higher many-body terms. n > 1 is recommended both in terms of accuracy and efficiency of MFCC. For neutral protein side-chains, the computed PL interaction energy is visibly independent of the fragment length n. The MFCC fractionation error is determined by comparison to a full-system calculation for the 1060 atoms containing PL complex. For charged amino acid side-chains, the variation of the MFCC result with n is increased. For these systems, using a continuum solvation model with a dielectricity constant typical for protein environments (ϵ = 4) reduces both the variation with n and improves the stability of the DFT calculations considerably. The PL interaction energies for two typical complexes obtained ab initio for the first time are found to be rather large (-30 and -54 kcal/mol).

Protein-ligand interaction energies with dispersion corrected density functional theory and high-level wave function based methods.

With dispersion-corrected density functional theory (DFT-D3) intermolecular interaction energies for a diverse set of noncovalently bound protein-ligand complexes from the Protein Data Bank are calculated. The focus is on major contacts occurring between the drug molecule and the binding site. Generalized gradient approximation (GGA), meta-GGA, and hybrid functionals are used. DFT-D3 interaction energies are benchmarked against the best available wave function based results that are provided by the estimated complete basis set (CBS) limit of the local pair natural orbital coupled-electron pair approximation (LPNO-CEPA/1) and compared to MP2 and semiempirical data. The size of the complexes and their interaction energies (ΔE(PL)) varies between 50 and 300 atoms and from -1 to -65 kcal/mol, respectively. Basis set effects are considered by applying extended sets of triple- to quadruple-ζ quality. Computed total ΔE(PL) values show a good correlation with the dispersion contribution despite the fact that the protein-ligand complexes contain many hydrogen bonds. It is concluded that an adequate, for example, asymptotically correct, treatment of dispersion interactions is necessary for the realistic modeling of protein-ligand binding. Inclusion of the dispersion correction drastically reduces the dependence of the computed interaction energies on the density functional compared to uncorrected DFT results. DFT-D3 methods provide results that are consistent with LPNO-CEPA/1 and MP2, the differences of about 1-2 kcal/mol on average (<5% of ΔE(PL)) being on the order of their accuracy, while dispersion-corrected semiempirical AM1 and PM3 approaches show a deviating behavior. The DFT-D3 results are found to depend insignificantly on the choice of the short-range damping model. We propose to use DFT-D3 as an essential ingredient in a QM/MM approach for advanced virtual screening approaches of protein-ligand interactions to be combined with similarly "first-principle" accounts for the estimation of solvation and entropic effects.

A consistent and accurate ab initio parametrization of density functional dispersion correction (DFT-D) for the 94 elements H-Pu.

The method of dispersion correction as an add-on to standard Kohn-Sham density functional theory (DFT-D) has been refined regarding higher accuracy, broader range of applicability, and less empiricism. The main new ingredients are atom-pairwise specific dispersion coefficients and cutoff radii that are both computed from first principles. The coefficients for new eighth-order dispersion terms are computed using established recursion relations. System (geometry) dependent information is used for the first time in a DFT-D type approach by employing the new concept of fractional coordination numbers (CN). They are used to interpolate between dispersion coefficients of atoms in different chemical environments. The method only requires adjustment of two global parameters for each density functional, is asymptotically exact for a gas of weakly interacting neutral atoms, and easily allows the computation of atomic forces. Three-body nonadditivity terms are considered. The method has been assessed on standard benchmark sets for inter- and intramolecular noncovalent interactions with a particular emphasis on a consistent description of light and heavy element systems. The mean absolute deviations for the S22 benchmark set of noncovalent interactions for 11 standard density functionals decrease by 15%-40% compared to the previous (already accurate) DFT-D version. Spectacular improvements are found for a tripeptide-folding model and all tested metallic systems. The rectification of the long-range behavior and the use of more accurate C(6) coefficients also lead to a much better description of large (infinite) systems as shown for graphene sheets and the adsorption of benzene on an Ag(111) surface. For graphene it is found that the inclusion of three-body terms substantially (by about 10%) weakens the interlayer binding. We propose the revised DFT-D method as a general tool for the computation of the dispersion energy in molecules and solids of any kind with DFT and related (low-cost) electronic structure methods for large systems.

Cooperativity in noncovalent interactions of biologically relevant molecules.

Using a recently published benchmark MP2 database of nucleic acid base trimers, the three-body contribution to the interaction energy (TBE, also termed (non)cooperativity) as a function of base composition and complex geometry is studied. In 28 out of 141 cases (or 20%), the counterpoise-corrected MP2/TZV(2df,2pd) TBE exceeds 1 kcal mol(-1). The TBE is below 1 kcal mol(-1) for all trimers in the benchmark set consisting of U, T, and A, irrespective of the geometrical arrangement in the database. The largest MP2/TZV(2df,2pd) cooperativity of -9 kcal mol(-1) is obtained for a hydrogen-bonded guanine trimer. The largest anti-cooperativity occurs for a protonated cytosine-guanine-cytosine trimer (6 kcal mol(-1)). Generally, the many-body non-additivity term is an order of magnitude smaller than the interaction energies (on average -33 kcal mol(-1)). Employing various density functionals (GGA, meta-GGA, and hybrid) and wave function methods up to third order perturbation theory, and using atomic-orbital basis sets of double-, triple-, and quadruple-zeta quality, we find that the non-additivity effects are almost independent of one particle basis set and method. To enable an interpretation of the TBE, the intermolecular interaction energy is subjected to an energy decomposition analysis (EDA) with a similar definition of the energy terms as the Morokuma decomposition scheme. We find that nonadditive effects are mainly due to the induction, while exchange repulsion, electrostatic, and dispersion contributions are essentially additive, the latter also beyond second order at the MP3/SV(d,p) level. The performance of dispersion-corrected density functional theory for the prediction of structures and binding energies is assessed. While an accurate reproduction of the MP2-optimized reference structures of the trimers can already be accomplished with modern density functionals, only the inclusion of the long-range (London) dispersion interaction provides a consistent picture for both structures and binding energies.

Analysis of non-covalent interactions in (bio)organic molecules using orbital-partitioned localized MP2.

Localized molecular orbitals (LMO) are used as basis for an MP2 treatment (LMP2) of electron correlation energies. The major aim is an improved understanding of the non-covalent interactions in large molecules with an emphasis on intra-molecular dispersion effects. A partitioning of the inter-fragment electron correlation energy into electron pairs of different orbital type (i.e., sigma, pi, lone-pairs) is presented. The benzene dimer, 1,4-diphenylbutane conformations, and the tyrosine-glycine dipeptide are used as model systems. For the benzene dimer, comparisons with CCSD(T) data are made in order to analyse the MP2 problems for pi-pi stacking. A comparison of phenyl-phenyl interactions in the benzene dimer and for 1,4-diphenylbutane conformations reveals a very good transferability of dispersion-type contributions to binding from an inter-molecular to an intra-molecular situation. In both systems, the relative (percentage) contributions of sigma-sigma, sigma-pi, and pi-pi pairs to the total inter-fragment correlation energy is a clear signature for the binding mode (pi-stacked vs. T-shaped). For various benzene dimer conformations, we find a linear relation between the MP2 interaction energy error and the correlation contribution from pi-pi pairs. In the dipeptide, also dispersion-type electron correlations between the glycyl amino acid residue and the phenol group are most relevant for folding. This convincingly explains problems of DFT with such systems reported previously. Although in this case only one aromatic ring (and a glycyl moiety) is involved, the same sigma-sigma, sigma-pi, and pi-pi correlations seem to dominate the shape of the potential energy surface.

Structures and interaction energies of stacked graphene-nucleobase complexes.

The noncovalent interactions of nucleobases and hydrogen-bonded (Watson-Crick) base-pairs on graphene are investigated with the DFT-D method, i.e., all-electron density functional theory (DFT) in generalized gradient approximation (GGA) combined with an empirical correction for dispersion (van der Waals) interactions. Full geometry optimization is performed for complexes with graphene sheet models of increasing size (up to C(150)H(30)). Large Gaussian basis sets of at least polarized triple-zeta quality are employed. The interaction energies are extrapolated to infinite lateral size of the sheets. Comparisons are made with B2PLYP-D and SCS-MP2 single point energies for coronene and C(54)H(18) substrates. The contributions to the binding (Pauli exchange repulsion, electrostatic and induction, dispersion) are analyzed. At a frozen inter-fragment distance, the interaction energy surface of the rigid C(96)H(24) and base monomers is explored in three dimensions (two lateral and one rotational). Methodologically and also regarding the results of an energy decomposition analysis, the complexes behave like other pi-stacked systems examined previously. The sequence obtained for the interaction energy of bases with graphene (G > A > T > C > U) is the same for all methods and supports recent experimental findings. The absolute values are rather large (about -20 to -25 kcal mol(-1)) but in the expected range for pi-systems of that size. The relatively short equilibrium inter-plane distance (about 3 A) is consistent with atomic force microscopy results of monolayer guanine and adenine on graphite. In graphene ... Watson-Crick pair complexes, the bases lie differently from their isolated energy minima leading to geometrical anti-cooperativity. Together with an electronic contribution of 2 and 6%, this adds up to total binding anti-cooperativities of 7 and 12% for AT and CG, respectively, on C(96)H(24). Hydrogen bonds themselves are merely affected by binding on graphene.

Is spin-component scaled second-order Møller-Plesset perturbation theory an appropriate method for the study of noncovalent interactions in molecules?

Testing of the spin-component scaled second-order Møller-Plesset (SCS-MP2) method for the computation of noncovalent interaction energies is done with a database of 165 biologically relevant complexes. The effects of the spin-scaling procedure (i.e., MP2 vs SCS-MP2), the basis set size, and the corrections for basis set superposition error (BSSE) are systematically examined. When using two-point basis set extrapolations for the correlation energy, augmentation of the atomic orbital basis with computationally costly diffuse functions is found to be obsolete. In general, SCS-MP2 also improves results for noncovalent interactions statistically on MP2, and significant outliers are removed. Moreover, it is shown that effects of BSSE and one-particle basis set incompleteness almost cancel each other in the case of triple-zeta sets (SCS-MP2/TZVPP or SCS-MP2/cc-pVTZ without counterpoise correction), which opens a practical route to efficient computations for large systems. We recommend SCS-MP2 as the preferred quantum chemical wave function based method for the noncovalent interactions in large biologically relevant systems when reasonable coupled-cluster with single and double and perturbative triple excitations (CCSD(T)) calculations cannot be performed anymore. A comparison to MP2 and CCSD(T) interaction energies for n-alkane dimers, however, indicates (and this also holds to a lesser extent for hydrogen-bonded systems) limitations of SCS-MP2 when treating chemically "saturated" interactions. The different behavior of second-order perturbation theory for saturated and for stacked pi-systems is discussed.

Density functional theory with dispersion corrections for supramolecular structures, aggregates, and complexes of (bio)organic molecules.

Kohn-Sham density functional theory (KS-DFT) is nowadays the most widely used quantum chemical method for electronic structure calculations in chemistry and physics. Its further application in e.g. supramolecular chemistry or biochemistry has mainly been hampered by the inability of almost all current density functionals to describe the ubiquitous attractive long-range van der Waals (dispersion) interactions. We review here methods to overcome this defect, and describe in detail a very successful correction that is based on damped -C(6).R(-6) potentials (DFT-D). As examples we consider the non-covalent inter- and intra-molecular interactions in unsaturated organic molecules (so-called pi-pi stacking in benzenes and dyes), in biologically relevant systems (nucleic acid bases/pairs, proteins, and 'folding' models), between fluorinated molecules, between curved aromatics (corannulene and carbon nanotubes) and small molecules, and for the encapsulation of methane in water clusters. In selected cases we partition the interaction energies into the most relevant contributions from exchange-repulsion, electrostatics, and dispersion in order to provide qualitative insight into the binding character.

Density functional theory including dispersion corrections for intermolecular interactions in a large benchmark set of biologically relevant molecules.

Density functional theory including dispersion corrections (DFT-D) is applied to calculate intermolecular interaction energies in an extensive benchmark set consisting mainly of DNA base pairs and amino acid pairs, for which CCSD(T) complete basis set limit estimates are available (JSCH-2005 database). The three generalized gradient approximation (GGA) density functionals B-LYP, PBE and the new B97-D are tested together with the popular hybrid functional B3-LYP. The DFT-D interaction energies deviate on average by less than 1 kcal mol(-1) or 10% from the reference values. In only six out of 161 cases, the deviation exceeds 2 kcal mol(-1). With one exception, the few larger deviations occur for non-equilibrium structures extracted from experimental geometries. The largest absolute deviations are observed for pairs of oppositely charged amino acids which are, however, not significant on a relative basis due to the huge interaction energies > 100 kcal mol(-1) involved. The counterpoise (CP) correction for the basis set superposition error with the applied triple-zeta AO basis sets varies between 0 and -1 kcal mol(-1) (<5% of the interaction energy in most cases) except for four complexes, where it is up to -1.4 kcal mol(-1). It is thus suggested to skip the laborious calculation of the CP correction in DFT-D treatments with reasonable basis sets. The three dispersion corrected GGAs considered differ mainly for the interactions of the hydrogen-bonded DNA base pairs, which are systematically too small by 0.6 kcal mol(-1) in case of B97-D, while for PBE-D they are too high by 1.5 kcal mol(-1), and for B-LYP-D by 0.5 kcal mol(-1). The all in all excellent results that have been obtained at affordable computational costs suggest the DFT-D method to be a routine tool for many applications in organic chemistry or biochemistry.

Anharmonic midinfrared vibrational spectra of benzoic acid monomer and dimer.

Anharmonic vibrational calculations for the benzoic acid monomer and dimer in the mid-IR regime (500-1800 cm(-1)) are reported. Harmonic frequencies and intensities are obtained at the DFT/B3LYP level of theory employing D95(d,p) and cc-pVTZ basis sets. Anharmonic corrections obtained from standard perturbation theory lead to redshifts of 1%-3%. In almost all cases, the resulting frequencies deviate by less than 1% from previous measurements [Bakker et al., J. Chem. Phys. 119, 11180 (2003)]. Calculated intensities are in qualitative agreement with the absorption experiment, with the cc-pVTZ values being superior to the D95(d,p) ones for a few modes of the dimer. The antisymmetric out-of-plane bending mode of the dimer, which is strongly blueshifted with respect to the monomer frequency, represents a remarkable exception: The harmonic frequencies obtained for the two basis sets differ notably from each other, and the anharmonically corrected frequencies deviate from the experimental value by 8% [D95(d,p)] or 3% (cc-pVTZ). Nonperturbative calculations in reduced dimensionality reveal that the relatively small total anharmonic shift (few tens of cm(-1)) comprises of partly much larger contributions (few hundreds of cm(-1)) which are mostly canceling each other. Many of the individual anharmonic couplings are beyond the validity of second-order perturbation theory based on cubic and semidiagonal quartic force constants only. This emphasizes the need for high-dimensional, nonperturbative anharmonic calculations at high quantum-chemical level when accurate frequencies of H-atom vibrations in double hydrogen bonds are sought for.

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.

Nonadiabatic effects on peptide vibrational dynamics induced by conformational changes.

Quantum dynamical simulations of vibrational spectroscopy have been carried out for glycine dipeptide (CH(3)-CO-NH-CH(2)-CO-NH-CH(3)). Conformational structure and dynamics are modeled in terms of the two Ramachandran dihedral angles of the molecular backbone. Potential energy surfaces and harmonic frequencies are obtained from electronic structure calculations at the density functional theory (DFT) [B3LYP/6-31+G(d)] level. The ordering of the energetically most stable isomers (C(7) and C(5)) is reversed upon inclusion of the quantum mechanical zero point vibrational energy. Vibrational spectra of various isomers show distinct differences, mainly in the region of the amide modes, thereby relating conformational structures and vibrational spectra. Conformational dynamics is modeled by propagation of quantum mechanical wave packets. Assuming a directed energy transfer to the torsional degrees of freedom, transitions between the C(7) and C(5) minimum energy structures occur on a sub-picosecond time scale (700...800 fs). Vibrationally nonadiabatic effects are investigated for the case of the coupled, fundamentally excited amide I states. Using a two state-two mode model, the resulting wave packet dynamics is found to be strongly nonadiabatic due to the presence of a seam of the two potential energy surfaces. Initially prepared adiabatic vibrational states decay upon conformational change on a time scale of 200...500 fs with population transfer of more than 50% between the coupled amide I states. Also the vibrational energy transport between localized (excitonic) amide I vibrational states is strongly influenced by torsional dynamics of the molecular backbone where both enhanced and reduced decay rates are found. All these observations should allow the detection of conformational changes by means of time-dependent vibrational spectroscopy.