Comparative performance assessment of the conformational model generators omega and catalyst: a large-scale survey on the retrieval of protein-bound ligand conformations

In continuation of our studies to evaluate the ability of various conformer generators to produce bioactive conformations, we present the extension of our work on the analysis of Catalyst's conformational subsampling algorithm in a comparative evaluation with OpenEye's currently updated tool Omega 2.0. Our study is based on an enhanced test set of 778 drug molecules and pharmacologically relevant compounds extracted from the Protein Data Bank (PDB). We elaborated protocols for two common conformer generation use cases and applied them to both programs: (i) high-throughput settings for processing large databases and (ii) high-quality settings for binding site exploration or lead structure refinement. While Catalyst is faster in the first case, Omega 2.0 better reproduces the bound ligand conformations from the PDB in less time for the latter case.     

Reproducing the conformations of protein-bound ligands: a critical evaluation of several popular conformational searching tools

Several programs (Catalyst, Confort, Flo99, MacroModel, and Omega) that are commonly used to generate conformational ensembles have been tested for their ability to reproduce bioactive conformations. The ligands from thirty-two different ligand–protein complexes determined by high-resolution (le2.0 Å) X-ray crystallography have been analyzed. The Low-Mode Conformational Search method (with AMBER^* and the GB/SA hydration model), as implemented in MacroModel, was found to perform better than the other algorithms. The rule-based method Omega, which is orders of magnitude faster than the other methods, also gave reasonable results but were found to be dependent on the input structure. The methods supporting diverse sampling (Catalyst, Confort) performed least well. For the seven ligands in the set having eight or more rotatable bonds, none of the bioactive conformations were ever found, save for one exception (Flo99). These ligands do not bind in a local minimum conformation according to AMBER^*\GB/SA. Taking these last two observations together, it is clear that geometrically similar structures should be collected in order to increase the probability of finding the bioactive conformation among the generated ensembles. Factors influencing bioactive conformational retrieval have been identified and are discussed.     

Comparative study of several algorithms for flexible ligand docking

We have performed a comparative assessment of several programs for flexible molecular docking: DOCK 4.0, FlexX 1.8, AutoDock 3.0, GOLD 1.2 and ICM 2.8. This was accomplished using two different studies: docking experiments on a data set of 37 protein-ligand complexes and screening a library containing 10,037 entries against 11 different proteins. The docking accuracy of the methods was judged based on the corresponding rank-one solutions. We have found that the fraction of molecules docked with acceptable accuracy is 0.47, 0.31, 0.35, 0.52 and 0.93 for, respectively, AutoDock, DOCK, FlexX, GOLD and ICM. Thus ICM provided the highest accuracy in ligand docking against these receptors. The results from the other programs are found to be less accurate and of approximately the same quality. A speed comparison demonstrated that FlexX was the fastest and AutoDock was the slowest among the tested docking programs. The database screening was performed using DOCK, FlexX and ICM. ICM was able to identify the original ligands within the top 1% of the total library in 17 cases. The corresponding number for DOCK and FlexX was 7 and 8, respectively. We have estimated that in virtual database screening, 50% of the potentially active compounds will be found among approximately 1.5% of the top scoring solutions found with ICM and among approximately 9% of the top scoring solutions produced by DOCK and FlexX.     

A full conformational space analysis of bilirubin

Ab initio methods were utilized in a gas-phase systematic conformational search of bilirubin conformers. The whole molecule was divided into four fragments. Most stable conformers of them were employed to build 196 conformers of the complete bilirubin molecule. Initial geometries were optimized using HF/3-21G level of theory and the minimum energy conformers were then reoptimized at B3LYP/6-31G(d) level. Ridge-tile conformer was the most stable one, in perfect agreement with X-ray data. We found that while tetrapyrrole backbone shows some flexibility, propionic acid side chains have a greater influence in bilirubin conformation because they can interact through different hydrogen bond patterns with the backbone and between them.     

Automated conformational analysis: Algorithms for the efficient construction of low-energy conformations

Summary The method of constructing low-energy conformations using template joining can provide an efficient means of searching the conformational space of molecules. The simplest algorithm to perform this task would construct each potential conformation from scratch. However, new algorithms, some of which use techniques from Artificial Intelligence, have been developed which can greatly improve the efficiency of this approach.     

Comparative conformational analysis of peptide T analogs

A series of peptide T analogs were investigated within the molecular mechanics framework. In order to determine the role of the aminoacid residues in spatial formation of peptide T the conformational peculiarities of the glycine-substituted analogs were investigated. The conformational profiles of some biologically tested analogs of this peptide were determined independently. The received data permit to assess the active form of this peptide. It is characterized by β-turn at the C-terminal physiologically active pentapeptide fragment of peptide molecule. The received results are important for the investigation of the structure-activity relationship and may be used at design of a rigid-molecule drug against HIV.     

Geometric algorithms for the conformational analysis of long protein loops

The efficient filtering of unfeasible conformations would considerably benefit the exploration of the conformational space when searching for minimum energy structures or during molecular simulation. The most important conditions for filtering are the maintenance of molecular chain integrity and the avoidance of steric clashes. These conditions can be seen as geometric constraints on a molecular model. In this article, we discuss how techniques issued from recent research in robotics can be applied to this filtering. Two complementary techniques are presented: one for conformational sampling and another for computing conformational changes satisfying such geometric constraints. The main interest of the proposed techniques is their application to the structural analysis of long protein loops. First experimental results demonstrate the efficacy of the approach for studying the mobility of loop 7 in amylosucrase from Neisseria polysaccharea. The supposed motions of this 17-residue loop would play an important role in the activity of this enzyme.     

Systematic convergence of energies with respect to basis set and treatment of electron correlation: focal-point conformational analysis of methanol

A practical means of overcoming the limitation in accuracy of conformational analysis due to incompleteness of basis sets used in ab initio calculations involves calculating the energy with a series of systematically improving basis sets and extrapolating to the basis set limit. We report here a focal-point conformational analysis for methanol. The Hartree–Fock energy converges exponentially to the basis set limit, while the convergence of second-order correlation energy is well described by the formula . This formula also describes well the convergence of fourth-order correlation energy. The height of the rotational barrier at the Hartree–Fock level can be obtained reliably by taking the difference of the extrapolated energies of the two conformations and correcting the difference for correlation effects. Electron correlation has only a small decreasing effect on the height of the rotational barrier in methanol. The focal-point value for the torsional barrier in methanol is 0.999±0.007 kcal/mol. Acknowledgement.This project was supported by Provost Funds at University of California, Santa Barbara (UCSB). The computational resources were provided partially by the National Computational Science Alliance and UCSBs Supercomputer Facility. We also acknowledge the Horgan Award (University of Missouri-Columbia) to K. K., which made possible the purchase of additional computational resources. We thank Robert Gdanitz and Bernie Kirtman for valuable discussions and Jozef Noga for providing us with a copy of the DIRCCR12-OS program.     

Comparative conformational analysis of 1,3-dioxane and 1,3-dithiane

It was shown by ab initio quantum-chemical approximations HF/6-31G(d) and MP2/6-31G(d)//HF/6-31G(d) that the conformational isomerization of 1,3-dioxane and 1,3-dithiane proceeded along common routes. The potential energy surface of both compounds contains six minima including the chair invertomers and enantiomeric flexible forms. They are separated by several potential barriers. It was established by molecular dynamics method that the flexible conformers at heating and keeping at 295–300 K transformed into each other and in the chair conformer.     

Assessing the similarity of ligand binding conformations with the Contact Mode Score

Structural and computational biologists often need to measure the similarity of ligand binding conformations. The commonly used root-mean-square deviation (RMSD) is not only ligand-size dependent, but also may fail to capture biologically meaningful binding features. To address these issues, we developed the Contact Mode Score (CMS), a new metric to assess the conformational similarity based on intermolecular protein-ligand contacts. The CMS is less dependent on the ligand size and has the ability to include flexible receptors. In order to effectively compare binding poses of non-identical ligands bound to different proteins, we further developed the eXtended Contact Mode Score (XCMS). We believe that CMS and XCMS provide a meaningful assessment of the similarity of ligand binding conformations. CMS and XCMS are freely available at http://brylinski.cct.lsu.edu/content/contact-mode-score and http://geaux-computational-bio.github.io/contact-mode-score/.     

On the contribution of intramolecular H-bonding entropy to the conformational stability of alanine conformations

The experimental and theoretical rotamerization constants for the rotameric equilibrium between the two most stable conformations of the alpha-amino acid alanine are compared. The experimental technique of matrix-isolation Fourier transform infrared spectroscopy in combination with the density functional theory (DFT) (B3LYP) and the 6-31++G** basis set is used for this study. A large disagreement between the experimental and theoretical value of the equilibrium constant is found. A relatively strong intramolecular H-bond in conformation II is at the origin of this discrepancy. From the difference between the experimental and theoretical rotamerization constant, a DeltaS degrees value of -6.6 J K(-1) mol(-1) is found for the intramolecular H-bond formation.     

Theoretical study of the conformations of triosmium clusters with a chiral carane ligand

A theoretical study has been performed to investigate the conformations of triosmium clusters with a chiral carane ligand . The potential curves of internal rotation have been determined for organic ligands rotating around the S-C bond in the cluster complexes. The structures of possible conformers are analyzed along with reasons for their stability. The rotation barrier relative to the S-C bond is 439.8 kJ/mole, which hinders free rotation of ligands.Original Russian Text Copyright © 2004 by V. A. Potemkin V. A. Maksakov, and V. P. KirinTranslated from Zhurnal Strukturnoi Khimii, Vol. 45, No. 3, pp. 430–434, May–June, 2004.     

A critical comparison of search algorithms applied to the optimization of protein side-chain conformations

Three different optimization algorithms are applied to solving the problem of finding the best side-chain conformations with a test set of 14 globular proteins having known crystallographic conformations. It is shown that simulated annealing, simple and modified genetic algorithms, and a heuristic combinatorial approach achieve similar optimal solutions, with the exception of simulated annealing applied to the largest proteins. The efficiency of the different algorithms, however, shows wide variations. General conclusions are drawn concerning the optimal approach to such problems. © 1993 John Wiley & Sons, Inc.     

Locked conformations for proline pyrrolidine ring: synthesis and conformational analysis of cis- and trans-4-tert-butylprolines

The motional restrictions of the proline pyrrolidine ring allow this secondary amine amino acid to act as a turn inducer in many peptides and proteins. The pyrrolidine ring is known to exhibit two predominant pucker modes (i.e., C-4 (Cgamma) exo and endo envelope conformers whose ratio can be controlled by proper substituents in the ring). In nature, the exo puckered 4(R)-hydroxy-l-proline plays a crucial role as a building block in collagen and collagen-like structures. It has been previously concluded that the electronegativity of the 4-cis-substituent increases the endo puckering while the electronegativity of the 4-trans-substituent favors the exo puckering. Here, we have introduced a sterically demanding tert-butyl group at C-4 in trans- and cis-configurations. In the case of trans-substitution, the induced puckering effect on the pyrrolidine ring was studied with X-ray crystallography and 1H NMR spectral simulations. Both cis- and trans-4-tert-butyl groups strongly favor pseudoequatorial orientation, thereby causing opposite puckering effects for the pyrrolidine ring, cis-exo and trans-endo for l-prolines, in contrast to the effects observed in the case of electronegative C-4 substituents. The syntheses and structural analysis are presented for the conformationally constrained 4-tert-butylprolines. The prolines were synthesized from 4-hydroxy-l-proline, substitution with t-BuCuSPhLi being the key transformation. This reaction gave N-Boc-trans-4-tert-butyl-l-proline tert-butyl ester in 94% ee and 57% de. Enantioselectivity was increased to 99.2% ee by crystallization of N-Boc-trans-4-tert-butyl-l-proline in the final step of the synthesis.     

Selection of short-lived isotopes for activation analysis with respect to sensitivity

During the last decade the use of short-lived isotopes in activation analysis has exploded, owing to the application of high resolution gamma-ray spectrometry. Complex spectra can in fact be resolved without the need for chemical separations. The application of cyclic activation-counting enables the use of isotopes with half-lives below 10 seconds. These short-lived isotopes can be produced by different activation processes. As neutron sources one can distinguish reactors, generators for 14 MeV or high energy machines such as cyclotrons and isotopic neutron sources. High energy photons can be produced by interaction of an energetic electron beam with a target, giving rise to an intense bremsstrahlung spectrum with maximum energy from 10 up to 70 MeV. While these photons induce several types of threshold reactions, lower energetic photons are used for resonance activation producing metastable isomers. More and more also charged particles (p, d,³He, α) are being used as projectiles to produce radioactive isotopes that can be measured in activation analysis. In the present paper a concise compilation is made of the nuclear reactions, applicable in activation analysis of minor or trace constituents using gamma emitting isotopes with half-lived smaller than 1 hour. Activations of all naturally occurring elements, except the noble gases, with Z values ranging from 9 to 92 have been considered. The reactions resulting in the most sensitive gammaspectroscopic determinations have been selected and are tabulated per element, together with the appropriate cross section and the resonance integral if significant for neutron reactions, the cross section at the giant resonance energy for the photon and at the maximum of the excitation function for the charged particle reactions and the threshold energy for all threshold reactions. For each isotope produced the half-life and the major gamma-ray energy is given. Finally calculated or experimental sensitivities have been compiled from a number of references, as the emission rate per second of the most intense gamma-ray, at the end of a 1 minute irradiation under well-defined circumstances for 1 microgram of the element. When cyclic activation has been applied it is indicated. These data are provided for more than 200 nuclear reactions. It appears that the majority of the 70 elements constacred can in some way be determined with a high sensitivity after such a short irradiation. Only for the elements Tm and Tb no reaction yielding a short-lived isotope with a reasonable sensitivity could be found. Both elements can however very sensitively be determined after a longer neutron irradiation. For a number of elements activation analysis by means of the middle-long-lived isotopes (2 hours to 3 days) is the most sensitive even after a 1 minute irradiation and immediate count (Mn, Ga, As, Sr, Ru, La, Eu, Ho, Lu, Os and Au). But for all other elements the highest gamma emission rate results from isotopes with half-lives shorter than 1 hour. Extremely high counting rates are obtained after thermal reactor neutron activation for Na, Sc, V, Co, Se, Rh, Ag, In, Eu, Dy, Er and Hf. For a number of elements the selectivity of the analysis can however largely be enhanced by irradiation under Cd-cover. High σ₀ ratios exist in fact for activation of medium and high Z elements such as Nb, Rb, Rh, Sn, Sb, Ba, Ce, Lu, Ta, Os, Hg and U. For some elements activation with reactor fission neutrons or 14 MeV neutrons provides an interesting sensitivity for a threshold reaction or the production of an isomer (F, Si, P, Cl, Ca, Cr, Se, Y, Ba, Ce, Pr, Bi, Pb). Cyclic activation and counting of very short-lived isotopes has been applied advantageously in the ng to μg range for a number of elements. Also cyclic activation with a 14 MeV generator has recently been studied. Low energy photon activation analysis allows selective production of metastable isomers of Se, Br, Ag, Er, Hf, Ir and Au, while high energetic photon production analysis yields high specific activities for elements such as K, Cr, Se, Br, Mo, Pr, Nd, Ho and allows interesting determinations of Mg, Cl, Si, Cr, Fe, Zr and Pb. Also charged particle activation can be used with surprisingly high sensitivity for some medium and high Z elements (Cr, Y, Se, Br, Zr, Mo, La, Ta, V). The intensity of the irradiation is in these cases mostly only limited by the properties of the sample itself, such as heat transfer and matrix activity. Examples of the compilation will be discussed and applications shown.     

Comparative conformational analysis between an undecamer of DNA and its apurinic homologue

Molecular modeling of a DNA undecamer and a corresponding DNA apurinic undecamer (d(CGCACXCACGC) d(GCGTGTGTGCG), X = A or apurinic site) has been performed using the jumna program. Among the possible structures, several are slightly distorted and correctly fit the experimental data obtained from NMR measurements. In these structures, the thymine base that faces the apurinic site lies inside the double helix.     

Cluster analysis of periodic distributions; application to conformational analysis

A method is described to analyze observed conformations for molecular fragments with more than three torsional degrees of freedom. The method is an adaption of statistical cluster analysis to multidimensional, symmetric, periodic distributions of data points. Application to the molecular fragment M(PPh₃)₂ with eight torsional degrees of freedom reveals a model of conformational interconversion. The model implies gearing motion of the two PC₃ fragments alternating with stepwise inversions of the helicities of the PPh₃-propellers.     

Theoretical study of the conformational states of triosmium clusters with a chiral pinane ligand

A theoretical study of the conformational state of triosmium clusters with a chiral pinane ligand (μ-H)Os₃(CO)₁₀(μ-ONC₁₀H₁₄) has been performed. The potential curves of internal rotation of organic ligands around the N-C bond in cluster complexes in the crystalline state and in various solvents with continual consideration for the parameters of the latter have been determined. The structures of conceivable conformers and isomers are considered; the factors responsible for their formation and stability are examined. The relations between the conformational and crystalline structures of the cluster and the effect of intra-and intermolecular interactions on its structure are revealed.     

Construction of half-sandwich rhodium- and iridium-based metallamacrocycles with different space conformations via isomeric pyridyl-substituted ligands

Abstract

Herein, we describe the utilization of isomeric pyridyl-substituted ligands featuring different coordination vectors to rationally design and construct a series of discrete organometallic assemblies with specific space conformations. In the case of tetranuclear macrocycles constructed from the ligand 3-bpb, different conformations of these assemblies with C_2v and C_2 h point symmetry were revealed by single-crystal X-ray diffraction. These complexes were further characterized by X-ray crystallography, ¹H NMR, DOSY NMR, IR spectroscopy, and elemental analyses.     

A molecular mechanics approach to mapping the conformational space of diaryl and triarylphosphines

A molecular mechanics force field has been developed which accurately reproduces experimental solid state structures and conformer interconversion barriers for a series of sterically congested diaryl and triaryl phosphines and some of their chalcogenide and Cr(CO)5 derivatives.