title: A New Method for Navigating Optimal Direction for Pulling Ligand from Binding Pocket: Application to Ranking Binding Affinity by Steered Molecular Dynamics.
abstract: In this paper we present a new method for finding the optimal path for pulling a ligand from the binding pocket using steered molecular dynamics (SMD). Scoring function is defined as the steric hindrance caused by a receptor to ligand movement. Then the optimal path corresponds to the minimum of this scoring function. We call the new method MSH (Minimal Steric Hindrance). Contrary to existing navigation methods, our approach takes into account the geometry of the ligand while other methods including CAVER only consider the ligand as a sphere with a given radius. Using three different target + receptor sets, we have shown that the rupture force Fmax and nonequilibrium work Wpull obtained based on the MSH method show a much higher correlation with experimental data on binding free energies compared to CAVER. Furthermore, Wpull was found to be a better indicator for binding affinity than Fmax. Thus, the new MSH method is a reliable tool for obtaining the best direction for ligand exiting from the binding site. Its combination with the standard SMD technique can provide reasonable results for ranking binding affinities using Wpull as a scoring function.
authors.affiliation: Institute for Computational Science and Technology, Tan Chanh Hiep Ward, District 12, Ho Chi Minh City, Vietnam.
authors.forename: Quan Van
authors.initials: QV
authors.lastname: Vuong
authors.affiliation: Institute for Computational Science and Technology, Tan Chanh Hiep Ward, District 12, Ho Chi Minh City, Vietnam.
authors.forename: Tin Trung
authors.initials: TT
authors.lastname: Nguyen
authors.affiliation: Institute for Computational Science and Technology, Tan Chanh Hiep Ward, District 12, Ho Chi Minh City, Vietnam.|Institute of Physics, Polish Academy of Sciences , Al. Lotnikow 32/46, 02-668 Warsaw, Poland.
authors.forename: Mai Suan
authors.initials: MS
authors.lastname: Li
mesh_terms: D001665:Binding Sites; D002623:Chemistry Techniques, Analytical / Q000379:methods*; D006801:Humans; D008024:Ligands; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D013816:Thermodynamics; D013917:Thrombin / Q000737:chemistry*
chemical_list: D008024:Ligands; D013917:Thrombin