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Funnel metadynamics as accurate binding free-energy method.

Proceedings of the National Academy of Sciences of the United States of America (2013-04-05)
Vittorio Limongelli, Massimiliano Bonomi, Michele Parrinello
ABSTRACT

A detailed description of the events ruling ligand/protein interaction and an accurate estimation of the drug affinity to its target is of great help in speeding drug discovery strategies. We have developed a metadynamics-based approach, named funnel metadynamics, that allows the ligand to enhance the sampling of the target binding sites and its solvated states. This method leads to an efficient characterization of the binding free-energy surface and an accurate calculation of the absolute protein-ligand binding free energy. We illustrate our protocol in two systems, benzamidine/trypsin and SC-558/cyclooxygenase 2. In both cases, the X-ray conformation has been found as the lowest free-energy pose, and the computed protein-ligand binding free energy in good agreement with experiments. Furthermore, funnel metadynamics unveils important information about the binding process, such as the presence of alternative binding modes and the role of waters. The results achieved at an affordable computational cost make funnel metadynamics a valuable method for drug discovery and for dealing with a variety of problems in chemistry, physics, and material science.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Benzamidine, ≥95.0%
Sigma-Aldrich
Benzamidine hydrochloride, 99%
Sigma-Aldrich
Trypsin from bovine pancreas, Type I, ~10,000 BAEE units/mg protein
Sigma-Aldrich
Trypsin from bovine pancreas, TPCK Treated, essentially salt-free, lyophilized powder, ≥10,000 BAEE units/mg protein
Sigma-Aldrich
Trypsin from bovine pancreas, suitable for protein sequencing, lyophilized powder
Sigma-Aldrich
Trypsin from bovine pancreas, essentially salt-free, lyophilized powder, ≥9,000 BAEE units/mg protein, BioReagent, suitable for cell culture
Sigma-Aldrich
Trypsin from bovine pancreas, ≥2,500 USP units/mg solid, meets USP testing specifications
Sigma-Aldrich
Trypsin from bovine pancreas, TPCK Treated, essentially salt-free, lyophilized powder, ≥10,000 BAEE units/mg protein
Sigma-Aldrich
Trypsin Acetylated from bovine pancreas, Type V-S, ≥8,500 BAEE units/mg protein (biuret)
Sigma-Aldrich
Cyclooxygenase 1 from sheep, glycerol solution, ≥1500 units/mg protein
Sigma-Aldrich
Trypsin from bovine pancreas, Type XI, lyophilized powder, ≥6,000 BAEE units/mg protein
Sigma-Aldrich
Trypsin from human pancreas, salt-free, lyophilized powder, vial of ≥1,000 BAEE units
Sigma-Aldrich
Trypsin from bovine pancreas, powder, ≥7,500 BAEE units/mg solid
Sigma-Aldrich
TrypZean® bovine, recombinant, expressed in corn, lyophilized powder, ≥3,350 units/mg solid (USP)
Sigma-Aldrich
Trypsin from porcine pancreas, tablet, 1 mg tablet
Sigma-Aldrich
Trypsin from porcine pancreas, lyophilized powder, Type II-S, 1,000-2,000 units/mg dry solid
Sigma-Aldrich
Trypsin from porcine pancreas, lyophilized powder, BioReagent, suitable for cell culture, 1,000-2,000 BAEE units/mg solid
Sigma-Aldrich
Trypsin from porcine pancreas, lyophilized powder, γ-irradiated, BioXtra, suitable for cell culture, 1,000-2,000 BAEE units/mg solid
Sigma-Aldrich
Trypsin from porcine pancreas, Type IX-S, lyophilized powder, 13,000-20,000 BAEE units/mg protein
Sigma-Aldrich
Benzamidine hydrochloride 1 M solution