Construction and test of ligand decoy sets using MDock: community structure-activity resource benchmarks for binding mode prediction

Two sets of ligand binding decoys have been constructed for the community structure-activity resource (CSAR) benchmark by using the MDock and DOCK programs for rigid- and flexible-ligand docking, respectively. The decoys generated for each complex in the benchmark thoroughly cover the binding site and also contain a certain number of near-native binding modes. A few scoring functions have been evaluated using the ligand binding decoy sets for their abilities of predicting near-native binding modes. Among them, ITScore achieved a success rate of 86.7% for the rigid-ligand decoys and 79.7% for the flexible-ligand decoys, under the common definition of a successful prediction as root-mean-square deviation <2.0 ? from the native structure if the top-scored binding mode was considered. The decoy sets may serve as benchmarks for binding mode prediction of a scoring function, which are available at the CSAR Web site ( http://www.csardock.org/).     

Binding and fluorescence study on interaction of human serum albumin (HSA) with cetylpyridinium chloride (CPC)

Human serum albumin (HSA) is frequently used in biophysical and biochemical studies since it has a well-known primary structure and it has been associated with the binding of many different categories of small molecules. In the present study, results are presented for the binding of cetylpyridinium chloride (CPC) with HSA at various pH and 25 degrees C, as monitored using ion selective membrane electrodes and fluorescence spectroscopy of intrinsic tryptophan. The obtained binding isotherms were analyzed on basis of binding capacity concept and Hill plot in order to determine the Hill parameters of binding sets. The system behaved as a system with two sets of binding sites in all studied situations. The results represent a positive cooperative behavior and the essential role of hydrophobic interactions in both binding sets. The intrinsic binding affinity of second binding set have a similar values and trends at acidic and neutral pHs, that represents the similar unfolded structure at these pHs. CPC quenched the fluorescence arising from Trp group incorporated to HSA. A biphasic behavior was observed in quenching process that confirmed the results of binding study correspond to the existence of two binding sets. The similarity of unfolded structure in acidic and neutral pH was also confirmed by fluorescence study. The quenching of HSA fluorescence takes place with a Stern-Volmer constant of 0.643 x 10(4), 1.23 x 10(4) and 7.40 x 10(4) at pH 3.5, 6.8 and 9.5, respectively. The Stern-Volmer behavior observed at low molar ratio of [CPC]/[HSA] (about 6), that represents the occurrence of conformational changes after this molar ratio. Comparing, the K(SV) values and binding parameters indicate that the binding is dominated by hydrophobic effects and, in minor degree, by electrostatic interactions.     

Thermochemistry and NBO analysis of peptide bond: Investigation of basis sets and binding energy

Ab initio methods were used to analyze the structure, energetic and binding energy of the five began dipeptides with methionine, Met-Gly, Met-Ala, Met-Ser, Met-Cys, and Met-Thr dipeptides, in gas phase. The structures of the dipetides and involved amino acids in them were optimized by using Hartree-Fock and DFT methods and 3-21G(d), 6-31G(d), 6-311G, 6-311G(d), and 6-311+G(d) basis sets. The effect of basis sets and electron correlations were analyzed with special emphasis on the calculated binding energies and thermodynamic functions. All used methods revealed that Met-Thr has the highest binding energy among all of the five dipeptide molecules. These numerical results suggest that Thr donates the proton easier than other four amino acids and it has the most tendency to join with methionine and it forms the most strong bond with methionine. This fact may be the reason behind the obtained high binding energies for Met-Thr at all levels. From comparison of the values of binding energy for dipeptides in different levels of theory, we could identify that the order of tendency for joint with methionine is Thr > Gly > Ala > Cys > Ser. Also, these data represented that the highest binding energy provide in HF/6-311G level for all of the dipeptides (14.4202, 11.2387, 8.3267, 9.8853, 17.3362 kcal mol⁻¹ for dipeptides 1–5, respectively). Moreover, natural bond orbital (NBO) analysis demonstrated that the effect of basis sets and electron correlations on σ_N1-C2 bonding orbital occupancy is the same as the basis set and electron correlation effects on binding energy of dipeptides in all cases. The obtained results from studying the effect of basis sets and electron correlations on binding energy, NMR and NBO properties showed that the effect of basis sets is almost independent of molecular structure and computational method, while electron correlation effects are relatively dependent to molecular structure and basis set type. In investigating the effect of basis sets and electron correlations on binding properties, the NBO results are in good agreement with the energetic and thermochemistry data at all levels of calculations. The article is published in the original.     

Assessing weak hydrogen binding on Ca+ centers: an accurate many-body study with large basis sets

Weak H(2) physisorption energies present a significant challenge to even the best correlated theoretical many-body methods. We use the phaseless auxiliary-field quantum Monte Carlo method to accurately predict the binding energy of Ca(+)-4H(2). Attention has recently focused on this model chemistry to test the reliability of electronic structure methods for H(2) binding on dispersed alkaline earth metal centers. A modified Cholesky decomposition is implemented to realize the Hubbard-Stratonovich transformation efficiently with large Gaussian basis sets. We employ the largest correlation-consistent Gaussian type basis sets available, up to cc-pCV5Z for Ca, to accurately extrapolate to the complete basis limit. The calculated potential energy curve exhibits binding with a double-well structure.     

Application of numerical basis sets to hydrogen bonded systems: a density functional theory study

We have investigated and compared the ability of numerical and Gaussian-type basis sets to accurately describe the geometries and binding energies of a selection of hydrogen bonded systems that are well studied theoretically and experimentally. The numerical basis sets produced accurate results for geometric parameters but tended to overestimate binding energies. However, a comparison of the time taken to optimize phosphinic acid dimer, the largest complex considered in this study, shows that calculations using numerical basis sets offer a definitive advantage where geometry optimization of large systems is required.     

Accurate ab initio binding energies of alkaline earth metal clusters

The effects of basis set superposition error (BSSE) and core-correlation on the electronic binding energies of alkaline earth metal clusters Y(n) (Y = Be, Mg, Ca; n = 2-4) at the Moller-Plesset second-order perturbation theory (MP2) and the single and double coupled cluster method with perturbative triples correction (CCSD(T)) levels are examined using the correlation consistent basis sets cc-pVXZ and cc-pCVXZ (X = D, T, Q, 5). It is found that, while BSSE has a negligible effect for valence-electron-only-correlated calculations for most basis sets, its magnitude becomes more pronounced for all-electron-correlated calculations, including core electrons. By utilizing the negligible effect of BSSE on the binding energies for valence-electron-only-correlated calculations, in combination with the negligible core-correlation effect at the CCSD(T) level, accurate binding energies of these clusters up to pentamers (octamers in the case of the Be clusters) are estimated via the basis set extrapolation of ab initio CCSD(T) correlation energies of the monomer and cluster with only the cc-pVDZ and cc-pVTZ sets, using the basis set and correlation-dependent extrapolation formula recently devised. A comparison between the CCSD(T) and density functional theory (DFT) binding energies is made to identify the most appropriate DFT method for the study of these clusters.     

Performance of numerical basis set DFT for aluminum clusters

We have investigated and compared the ability of numerical and Gaussian-type basis sets combined with density functional theory (DFT) to accurately describe the geometries, binding energies, and electronic properties of aluminum clusters, Al12XHn (X = Al, Si; n = 0, 1, 2). DFT results are compared against high-level benchmark calculations and experimental data where available. Properties compared include geometries, binding energies, ionization potentials, electron affinities, and HOMO-LUMO gaps. Generally, the PBE functional with the double numerical basis set with polarization (DNP) performs very well against experiment and the analytical basis sets for considerably less computational expense.     

Estimates of the ab initio limit for pi-pi interactions: the benzene dimer

State-of-the-art electronic structure methods have been applied to the simplest prototype of aromatic pi-pi interactions, the benzene dimer. By comparison to results with a large aug-cc-pVTZ basis set, we demonstrate that more modest basis sets such as aug-cc-pVDZ are sufficient for geometry optimizations of intermolecular parameters at the second-order M?ller-Plesset perturbation theory (MP2) level. However, basis sets even larger than aug-cc-pVTZ are important for accurate binding energies. The complete basis set MP2 binding energies, estimated by explicitly correlated MP2-R12/A techniques, are significantly larger in magnitude than previous estimates. When corrected for higher-order correlation effects via coupled cluster with singles, doubles, and perturbative triples [CCSD(T)], the binding energies D(e) (D(0)) for the sandwich, T-shaped, and parallel-displaced configurations are found to be 1.8 (2.0), 2.7 (2.4), and 2.8 (2.7) kcal mol(-1), respectively.     

PharmID: pharmacophore identification using Gibbs sampling

The binding of a small molecule to a protein is inherently a 3D matching problem. As crystal structures are not available for most drug targets, there is a need to be able to infer from bioassay data the key binding features of small molecules and their disposition in space, the pharmacophore. Fingerprints of 3D features and a modification of Gibbs sampling to align a set of known flexible ligands, where all compounds are active, are used to discern possible pharmacophores. A clique detection method is used to map the features back onto the binding conformations. The complete algorithm is described in detail, and it is shown that the method can find common superimposition for several test data sets. The method reproduces answers very close to the crystal structure and literature pharmacophores in the examples presented. The basic algorithm is relatively fast and can easily deal with up to 100 compounds and tens of thousands of conformations. The algorithm is also able to handle multiple binding mode problems, which means it can superimpose molecules within the same data set according to two different sets of binding features. We demonstrate the successful use of this algorithm for multiple binding modes for a set of D2 and D4 ligands.     

Electron Momentum Spectroscopy of Ethanethiol Complete Valence Shell

The binding energy spectra and electron momentum distributions for the complete valence orbitals of ethanethiol were measured for the first time by binary (e, 2e) electron momentum spectroscopy employing non-coplanar symmetric kinematics at an impact energy of 1200 eV plus binding energy. The experimental results are generally consistent with the theoretical calculations using density functional theory and Hartree-Fock methods with various basis sets. A possible satellite line at 17.8 eV in binding energy spectrum was observed and studied by electron momentum spectroscopy.     

Quantum chemistry benchmarking of binding and selectivity for lanthanide extractants

Computer‐aided screening methods facilitate the discovery of new extractants for heavy and rare‐earth metal separations. In this work, we have benchmarked the accuracy of different quantum chemistry methods for calculating extractant binding energies and selectivities. Specifically, we compare calculated data from different exchange correlation functionals (B3LYP‐D3, ωB97X‐D3, and M06‐L) and different basis sets (including large‐core effective core potentials and all‐electron basis sets). We report aqueous‐phase binding energy and selectivity trends for 1:1 and 3:1 extractant/lanthanide models for the complexes. We find that binding selectivities are not particularly sensitive to model chemistry, but binding energies are sensitive. Furthermore, calculated trends in selectivity using 3:1 extractant/lanthanide models are in better agreement with available experimental trends than trends using 1:1 extractant/lanthanide models. Lastly, we find that the B3LYP‐D3/6‐31 + G* model chemistry with the Stuttgart large‐core relativistic effective core potentials on the lanthanide sufficiently reproduces results from larger basis set calculations and is confirmed as suitable for relatively fast and efficient screening of lanthanide binding energies and selectivities.     

Accurate calculation of the binding energy of the water dimer

The binding energy of the water dimer is calculated at the MP2 level using efficient basis sets augmented with bond functions. The intermolecular energy is determined by the supermolecular approach and the basis set superposition error is corrected by the counterpoise method. Bond functions are found useful and very effective in recovering the dispersion energy, which is traditionally achieved by polarization functions. The calculated binding energy of the water dimer is systematically converged to a value of 4.75 kcal mol⁻ as bond functions are gradually added to nucleus-centered basis sets.     

Conformational changes and sequence analysis in cellulase from <Emphasis Type="Italic">Aspergillus niger</Emphasis> with cationic surfactant

The present study evaluates the binding of cetylpyridinium chloride (CPC) with cellulase in various experimental conditions using potentiometric, fluorescence spectroscopy and turbidimetric techniques. The analysis of binding curves revealed the existence of two sets of binding sets for CPC. The binding parameters were estimated and interpreted in terms of structural viewpoints of cellulase. The observation of turbidity suggests that CPC molecules individually nucleate around cellulase/CMC complex to form micelle-like structures. Fluorescence spectroscopy analysis of cellulase/CMC-surfactant system showed that these complexes could be compact to elucidate the mechanism of binding cellulase/CMC complex to CPC. The differential response of the enzyme/CMC to surfactant, indicates that the interaction on the complex surface is strongly ionic and hydrophobic(cooperative) in nature. A sequencing analysis was also conducted on β-1, 4-endoglucanase from A. niger (EglA) and others from family 12 in order to examine the nature of interaction involved in binding process and structure of carbohydrate-protein complexes. The results suggest that the conserved residues are located in a more hydrophobic microenvironment and apolar area energy is more than polar within enzyme structure.     

The Challenge of ab Initio Calculations in Small Neon Clusters

Weakly bound neon dimer, trimer and tetramers are studied at HF and CCSD(T) levels using Dunning, ANO and SIGMA-s basis sets. Their ground-state binding energies are studied along with some structural properties. SIGMA-s basis sets have been developed explicitly for this issue but in a manner that can be readily applied to other atoms for the study of larger weakly bound systems. The difficulties for attaining accurate results on these systems are assessed by the computation of total, atomization and correlation energies, as well as equilibrium distances, with several basis sets of increasing size, ranging from non-augmented to double-augmented versions. Extrapolations are proposed to predict stabilization energies and the results are compared with previously published data.     

Approximations to complete basis set-extrapolated, highly correlated non-covalent interaction energies

The first-principles calculation of non-covalent (particularly dispersion) interactions between molecules is a considerable challenge. In this work we studied the binding energies for ten small non-covalently bonded dimers with several combinations of correlation methods (MP2, coupled-cluster single double, coupled-cluster single double (triple) (CCSD(T))), correlation-consistent basis sets (aug-cc-pVXZ, X = D, T, Q), two-point complete basis set energy extrapolations, and counterpoise corrections. For this work, complete basis set results were estimated from averaged counterpoise and non-counterpoise-corrected CCSD(T) binding energies obtained from extrapolations with aug-cc-pVQZ and aug-cc-pVTZ basis sets. It is demonstrated that, in almost all cases, binding energies converge more rapidly to the basis set limit by averaging the counterpoise and non-counterpoise corrected values than by using either counterpoise or non-counterpoise methods alone. Examination of the effect of basis set size and electron correlation shows that the triples contribution to the CCSD(T) binding energies is fairly constant with the basis set size, with a slight underestimation with CCSD(T)∕aug-cc-pVDZ compared to the value at the (estimated) complete basis set limit, and that contributions to the binding energies obtained by MP2 generally overestimate the analogous CCSD(T) contributions. Taking these factors together, we conclude that the binding energies for non-covalently bonded systems can be accurately determined using a composite method that combines CCSD(T)∕aug-cc-pVDZ with energy corrections obtained using basis set extrapolated MP2 (utilizing aug-cc-pVQZ and aug-cc-pVTZ basis sets), if all of the components are obtained by averaging the counterpoise and non-counterpoise energies. With such an approach, binding energies for the set of ten dimers are predicted with a mean absolute deviation of 0.02 kcal/mol, a maximum absolute deviation of 0.05 kcal/mol, and a mean percent absolute deviation of only 1.7%, relative to the (estimated) complete basis set CCSD(T) results. Use of this composite approach to an additional set of eight dimers gave binding energies to within 1% of previously published high-level data. It is also shown that binding within parallel and parallel-crossed conformations of naphthalene dimer is predicted by the composite approach to be 9% greater than that previously reported in the literature. The ability of some recently developed dispersion-corrected density-functional theory methods to predict the binding energies of the set of ten small dimers was also examined.     

An ab initio study of intermolecular hydrogen bonding between small peptide fragments

Several small peptide fragments are investigated with ab initio (Hartree-Fock) calculations, using Gaussian basis sets. Complexation energies, net atomic charges, and optimum geometries are obtained. The geometries predicted by the STO -6G, and 6–31G* basis sets are quite similar, whereas the binding energies obtaiend by the 6–31G calculations are higher than those obtained with STO -6G and 6–31G* basis sets.     

Binding energy landscape analysis helps to discriminate true hits from high-scoring decoys in virtual screening

Although virtual screening through molecular docking has been widely applied in lead discovery, it is still challenging to distinguish true hits from high-scoring decoys because of the difficulty in accurately predicting protein-ligand binding affinities. Following the successful application of energy landscape analysis to both protein folding and biomolecular binding studies, we attempted to use protein-ligand binding energy landscape analysis to recognize true binders from high-scoring decoys. Two parameters describing the binding energy landscape were used for this purpose. The energy gap, defined as the difference between the binding energy of the native binding mode and the average binding energy of other binding modes in the "denatured binding phase", was used to describe the thermodynamic stability of binding, and the number of local binding wells in the landscapes was used to account for the kinetic accessibility. These parameters, together with the docking score, were combined using logistic regression to investigate their capability to discriminate true ligands from high-scoring decoys. Inhibitors and the noninhibitors of two enzyme systems, neuraminidase and cyclooxygenase-2, were used to test their discrimination capability. Using a five-fold cross-validation, the areas under the receiver operator characteristic curves (AUCs) from the best linear combinations of parameters reached 0.878 for neuraminidase and 0.776 for cyclooxygenase-2. To make a more independent test, inhibitors and high-scoring decoys in a directory of useful decoys (DUD), the largest and most comprehensive public data set for benchmarking virtual screen programs by far, were used as independent test sets to test the discrimination capability of these parameters. The AUCs of the best linear combinations of parameters for the independent test sets were 0.750 for neuraminidase and 0.855 for cyclooxygenase-2. Furthermore, combining these two parameters with the docking scoring function improved the enrichment ratio to 200-300% compared to that using the scoring function alone. This study suggests that incorporating information from binding energy landscape analysis can significantly increase the success rate of virtual screening.