Performance Evaluation of Docking Programs- Glide, GOLD, AutoDock & SurflexDock, Using Free Energy Perturbation Reference Data: A Case Study of Fructose-1, 6-bisphosphatase-AMP Analogs.

BACKGROUND: The accurate ranking of analogs of lead molecules with respect to their estimated binding free energies to drug targets remains highly challenging in molecular docking due to small relative differences in their free energy values. METHODS: Free energy perturbation (FEP) method, which provides the most accurate relative binding free energy values were earlier used to calculate free energies of many ligands for several important drug targets including Fructose-1,6-BisphosPhatase (FBPase). The availability of abundant structural and experimental binding affinity data for FBPase inhibitors provided an ideal system to evaluate four widely used docking programs, AutoDock, Glide, GOLD and SurflexDock, distinct from earlier comparative evaluation studies. RESULTS: The analyses suggested that, considering various parameters such as docking pose, scoring and ranking accuracy, sensitivity analysis and newly introduced relative ranking score, Glide provided reasonably consistent results in all respects for the system studied in the present work. Whereas GOLD and AutoDock also demonstrated better performance, AutoDock results were found to be significantly superior in terms of scoring accuracy compared to the rest. CONCLUSION: Present analysis serves as a useful guide for researchers working in the field of lead optimization and for developers in upgradation of the docking programs.

Thermal expansivity of amyloid beta(16-22) peptides and their aggregates in water.

Temperature dependence of the volumetric and structural properties of Abeta(16-22) peptides (wild type and pathogenic forms) and their aggregates in water was studied by simulations. The intrinsic thermal expansion coefficient alpha(p) of peptides was evaluated by taking into account the difference between the volumetric properties of hydration and bulk water. Single peptides show mainly positive values of alpha(p) that correlates with the increasing number of intrapeptide hydrogen bonds upon heating. Negative values of alpha(p) found for large peptide aggregates may be attributed to the shrinking of voids inside aggregates with increasing temperature or to their rubber-like elasticity. The peptide surface exposed to water becomes more hydrophobic with increasing aggregate size that appears in decreasing density of hydration water and evidences a hydrophilic character of aggregation.

Intrinsic thermal expansivity and hydrational properties of amyloid peptide Abeta42 in liquid water.

Volumetric and conformational properties of the amyloid beta(1-42) peptide (Abeta(42)) are studied in relation to the properties of hydration water in a wide temperature range by computer simulations. The apparent volume of Abeta(42), which is the change in the total volume of the solution due to the presence of Abeta(42), shows a quite different temperature dependence below and above T approximately 320 K. The apparent thermal expansion coefficient alpha(app)(Abeta(42)) is about 1.5x10(-3) K(-1) at T320 K. By evaluation of the thermal expansivity of hydration water, the intrinsic expansivity of the biomolecule in liquid water was determined for the first time. The intrinsic thermal expansion coefficient of Abeta(42) is found to be negative: alpha(int)(Abeta(42)) approximately -0.8x10(-3) K(-1). The negative thermal expansion coefficient of Abeta(42) can be attributed to its rubberlike (entropic) elasticity and/or to a decreasing number of intrapeptide hydrogen bonds. Upon heating, Abeta(42) transforms from an extended chain with a significant content of alpha-helices to a compact coil with noticeable content of beta-structures. A hydrogen-bonded spanning network of hydration water envelops Abeta(42) homogeneously at low temperatures but breaks into an ensemble of small water clusters upon heating via a percolation transition, whose midpoint is close to the temperature, where the apparent volume of Abeta(42) changes its temperature behavior. The mutual relation between the volumetric properties of Abeta(42), its conformational properties, and the properties of the hydration water is discussed.