Ensemble Of Low-energy Conformations Research Articles

Molecular Properties from Conformational Ensembles. 1. Dipole Moments of Molecules with Multiple Internal Rotations

We present a novel method for constructing the stable conformational space of small molecules with many rotatable bonds that uses our iterative stochastic elimination (ISE) algorithm, a robust stochastic search method capable of finding ensembles of best solutions for large combinatorial problems. To validate the method, we show that ISE reproduces the best conformers found in a fully exhaustive search, as well as compare computed dipole moments to experimental values, based on molecular ensembles and their Boltzmann distributions. Results were also compared to the alternative molecular dynamics and simulated annealing methods. Our results clarify that many low energy conformations may be required to reproduce molecular properties, while single low energy conformers or ensembles of low energy conformers cannot account for the experimental properties of flexible molecules. Whereas ISE well reproduces conformations that are not separated by very large energy barriers, it has not been successful in reproducing conformations of strained molecules.

Delineation of the Xrcc4-interacting Region in the Globular Head Domain of Cernunnos/XLF

In mammals, the majority of DNA double-strand breaks are processed by the nonhomologous end-joining (NHEJ) pathway, composed of seven factors: Ku70, Ku80, DNA-PKcs, Artemis, Xrcc4 (X4), DNA-ligase IV (L4), and Cernunnos/XLF. Cernunnos is part of the ligation complex, constituted by X4 and L4. To improve our knowledge on the structure and function of Cernunnos, we performed a systematic mutagenesis study on positions selected from an analysis of the recent three-dimensional structures of this factor. Ten of 27 screened mutants were nonfunctional in several DNA repair assays. Outside amino acids critical for the expression and stability of Cernunnos, we identified three amino acids (Arg(64), Leu(65), and Leu(115)) essential for the interaction with X4 and the proper function of Cernunnos. Docking the crystal structures of the two factors further validated this probable interaction surface of Cernunnos with X4.

Conformational Sampling for Large-Scale Virtual Screening: Accuracy versus Ensemble Size

We introduce the TrixX Conformer Generator (TCG), a novel tool for generating conformational ensembles. The tool addresses especially the requirements of large-scale computer-aided drug design applications using conformer databases. For these, the trade-off between accuracy, i.e. rmsd to biologically active conformers, and database size, i.e. the number of conformers in an ensemble, is of central interest. Based on a tree data structure representing the molecule, conformations are generated incrementally in a best-first-search build-up process employing an internal rmsd clustering. This way TCG builds conformational ensembles of low energy conformers utilizing conformational energy as a scoring function. A crucial parameter is the amount of search space to be covered in the build-up process. This parameter is determined according to an exponential function employing a user-specified quality level as base and an exponent which depends on the molecule's flexibility. The quality level allows the user to set the aforementioned trade-off while taking into account the exponentially growing number of combinations of torsion angles. Tested on a set of 778 molecules, we show that on average 20 conformers per ensemble suffice to achieve an average accuracy of 1.13 A. We observed that an improvement in accuracy goes along with an exponential rise of the number of conformations per ensemble (e.g., 100 conformations per ensemble yield an accuracy of 0.99 A). Furthermore, we show that for molecules with less than nine rotatable bonds, ensembles with an average accuracy better than 1 A can be generated with an average ensemble size of 20 conformers. However, this value deteriorates for more flexible molecules. A comparison to CATALYST and OMEGA shows that TCG achieves a comparable performance in terms of accuracy. Furthermore, it performs well with respect to the trade-off between accuracy and ensemble size.

Ab initio prediction of helical segments in polypeptides.

An ab initio method has been developed to predict helix formation for polypeptides. The approach relies on the systematic analysis of overlapping oligopeptides to determine the helical propensity for individual residues. Detailed atomistic level modeling, including entropic contributions, and solvation/ionization energies calculated through the solution of the Poisson-Boltzmann equation, is utilized. The calculation of probabilities for helix formation is based on the generation of ensembles of low energy conformers. The approach, which is easily amenable to parallelization, is shown to perform very well for several benchmark polypeptide systems, including the bovine pancreatic trypsin inhibitor, the immunoglobulin binding domain of protein G, the chymotrypsin inhibitor 2, the R69 N-terminal domain of phage 434 repressor, and the wheat germ agglutinin.

Gas phase conformations of biological molecules: the hydrogen/deuterium exchange mechanism

A model was developed to describe the deuterium uptake of gas phase polypeptide ions via H/D exchange with D 2O. Ab initio calculations established, for energetic reasons, that the exchange must take place via a “relay” mechanism involving both a charged site and a nearby basic site. Molecular dynamics simulations indicated that the D 2O molecule did not penetrate the core of the example peptide, protonated bradykinin (Bk+H) +, and hence the relay mechanism must occur on the peptide surface. Two factors were deemed to be important: (1) The surface accessibility of the charged sites and the basic sites and (2) the distances between them. An algorithm was developed that accounted for these features using the absolute exchange rate as a free parameter. Excellent agreement was obtained with experiment when equal weight was given to an ensemble of low energy conformations of (Bk+H) +, assumed to have a salt bridge primary structure. Single conformations, or other protonated forms, did not allow good agreement with experiment for any value of the absolute exchange rate constant.

Conformational analysis of platinum antitumor drugs

The purpose of this research is to effectively and efficiently search the conformational space of square planar Pt(II) antitumor drugs, using a combination of molecular mechanics, Monte Carlo (MC) and molecular dynamics (MD) methods. An MM2 force field for square planar Pt(II) complexes developed in our lab is extended to the related MM+ force field and shown to give equally reliable structural prediction. The reliability of the force field and three different conformational searching techniques (MC, MD and a random cartesian coordinate method (RCC)) are tested for cis-PtCl 2(NH 2R) 2 complexes. The MC and MD methods are found to be better than the RCC method for finding low-energy conformations. The conformational search results were used for a prototypical quantitative structure-activity relationship (QSAR) study and the results suggest that toxicity ( p( LD 50)) is reduced for complexes with larger volumes and surface areas. More importantly, the results show that molecular properties can be very geometry dependent, and hence an ensemble of low energy conformers must be considered for constructing QSARs for metal complexes with large and flexible ligands.