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Importance of ligand conformational energies in carbohydrate docking: Sorting the wheat from the chaff.

ABSTRACT: Docking algorithms that aim to be applicable to a broad range of ligands suffer reduced accuracy because they are unable to incorporate ligand-specific conformational energies. Here, we develop a set of Carbohydrate Intrinsic (CHI) energy functions that quantify the conformational properties of oligosaccharides, based on the values of their glycosidic torsion angles. The relative energies predicted by the CHI energy functions mirror the conformational distributions of glycosidic linkages determined from a survey of oligosaccharide-protein complexes in the protein data bank. Addition of CHI energies to the standard docking scores in Autodock 3, 4.2, and Vina consistently improves pose ranking of oligosaccharides docked to a set of anticarbohydrate antibodies. The CHI energy functions are also independent of docking algorithm, and with minor modifications, may be incorporated into both theoretical modeling methods, and experimental NMR or X-ray structure refinement programs.

SUBMITTER: Nivedha AK

PROVIDER: S-EPMC3936473 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Importance of ligand conformational energies in carbohydrate docking: Sorting the wheat from the chaff.

Nivedha Anita K AK Makeneni Spandana S Foley Bethany Lachele BL Tessier Matthew B MB Woods Robert J RJ

Journal of computational chemistry 20131229 7

Docking algorithms that aim to be applicable to a broad range of ligands suffer reduced accuracy because they are unable to incorporate ligand-specific conformational energies. Here, we develop a set of Carbohydrate Intrinsic (CHI) energy functions that quantify the conformational properties of oligosaccharides, based on the values of their glycosidic torsion angles. The relative energies predicted by the CHI energy functions mirror the conformational distributions of glycosidic linkages determi ...[more]

PMID: 24375430

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Project description:We present here a greatly updated version of an earlier study on the conformational energies of protein-ligand complexes in the Protein Data Bank (PDB) [Nicklaus et al. Bioorg. Med. Chem. 1995, 3, 411-428], with the goal of improving on all possible aspects such as number and selection of ligand instances, energy calculations performed, and additional analyses conducted. Starting from about 357,000 ligand instances deposited in the 2008 version of the Ligand Expo database of the experimental 3D coordinates of all small-molecule instances in the PDB, we created a "high-quality" subset of ligand instances by various filtering steps including application of crystallographic quality criteria and structural unambiguousness. Submission of 640 Gaussian 03 jobs yielded a set of about 415 successfully concluded runs. We used a stepwise optimization of internal degrees of freedom at the DFT level of theory with the B3LYP/6-31G(d) basis set and a single-point energy calculation at B3LYP/6-311++G(3df,2p) after each round of (partial) optimization to separate energy changes due to bond length stretches vs bond angle changes vs torsion changes. Even for the most "conservative" choice of all the possible conformational energies-the energy difference between the conformation in which all internal degrees of freedom except torsions have been optimized and the fully optimized conformer-significant energy values were found. The range of 0 to ~25 kcal/mol was populated quite evenly and independently of the crystallographic resolution. A smaller number of "outliers" of yet higher energies were seen only at resolutions above 1.3 Å. The energies showed some correlation with molecular size and flexibility but not with crystallographic quality metrics such as the Cruickshank diffraction-component precision index (DPI) and R(free)-R, or with the ligand instance-specific metrics such as occupancy-weighted B-factor (OWAB), real-space R factor (RSR), and real-space correlation coefficient (RSCC). We repeated these calculations with the solvent model IEFPCM, which yielded energy differences that were generally somewhat lower than the corresponding vacuum results but did not produce a qualitatively different picture. Torsional sampling around the crystal conformation at the molecular mechanics level using the MMFF94s force field typically led to an increase in energy.

Project description:Conventional methods for screening for stress-tolerant cereal varieties rely on expensive, labour-intensive field testing and molecular biology techniques. Here, we use the root hair assay (RHA) as a rapid screening tool to identify stress-tolerant varieties at the early seedling stage. Wheat and barley seedlings had stress applied, and the response quantified in terms of programmed cell death (PCD), viability and necrosis. Heat shock experiments of seven barley varieties showed that winter and spring barley varieties could be partitioned into their two distinct seasonal groups based on their PCD susceptibility, allowing quick data-driven evaluation of their thermotolerance at an early seedling stage. In addition, evaluating the response of eight wheat varieties to heat and salt stress allowed identification of their PCD inflection points (35°C and 150 mM NaCl), where the largest differences in PCD levels arise. Using the PCD inflection points as a reference, we compared different stress effects and found that heat-susceptible wheat varieties displayed similar vulnerabilities to salt stress. Stress-induced PCD levels also facilitated the assessment of the basal, induced and cross-stress tolerance of wheat varieties using single, combined and multiple individual stress exposures by applying concurrent heat and salt stress in a time-course experiment. Two stress-susceptible varieties were found to have low constitutive resistance as illustrated by their high PCD levels in response to single and combined stress exposure. However, both varieties had a fast, adaptive response as PCD levels declined at the other time-points, showing that even with low constitutive resistance, the initial stress cue primes cross-stress tolerance adaptations for enhanced resistance even to a second, different stress type. Here, we demonstrate the RHA's suitability for high-throughput analysis (∼4 days from germination to data collection) of multiple cereal varieties and stress treatments. We also showed the versatility of using stress-induced PCD levels to investigate the role of constitutive and adaptive resistance by exploring the temporal progression of cross-stress tolerance. Our results show that by identifying suboptimal PCD levels in vivo in a laboratory setting, we can preliminarily identify stress-susceptible cereal varieties and this information can guide further, more efficiently targeted, field-scale experimental testing.

Dataset Information

Importance of ligand conformational energies in carbohydrate docking: Sorting the wheat from the chaff.

Publications

Importance of ligand conformational energies in carbohydrate docking: Sorting the wheat from the chaff.

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