Principles of docking: An overview of search algorithms and a guide to scoring functions

Abstract

The docking field has come of age. The time is ripe to present the principles of docking, reviewing the current state of the field. Two reasons are largely responsible for the maturity of the computational docking area. First, the early optimism that the very presence of the "correct" native conformation within the list of predicted docked conformations signals a near solution to the docking problem, has been replaced by the stark realization of the extreme difficulty of the next scoring/ranking step. Second, in the last couple of years more realistic approaches to handling molecular flexibility in docking schemes have emerged. As in folding, these derive from concepts abstracted from statistical mechanics, namely, populations. Docking and folding are interrelated. From the purely physical standpoint, binding and folding are analogous processes, with similar underlying principles. Computationally, the tools developed for docking will be tremendously useful for folding. For large, multidomain proteins, domain docking is probably the only rational way, mimicking the hierarchical nature of protein folding. The complexity of the problem is huge. Here we divide the computational docking problem into its two separate components. As in folding, solving the docking problem involves efficient search (and matching) algorithms, which cover the relevant conformational space, and selective scoring functions, which are both efficient and effectively discriminate between native and non-native solutions. It is universally recognized that docking of drugs is immensely important. However, protein-protein docking is equally so, relating to recognition, cellular pathways, and macromolecular assemblies. Proteins function when they are bound to other molecules. Consequently, we present the review from both the computational and the biological points of view. Although large, it covers only partially the extensive body of literature, relating to small (drug) and to large protein-protein molecule docking, to rigid and to flexible. Unfortunately, when reviewing these, a major difficulty in assessing the results is the non-uniformity in the formats in which they are presented in the literature. Consequently, we further propose a way to rectify it here.

RA Differentiation Enhances Dopaminergic Features, Changes Redox Parameters, and Increases Dopamine Transporter Dependency in 6-Hydroxydopamine-Induced Neurotoxicity in SH-SY5Y Cells

“…Molecular docking was performed using Autodock4 and the protocol adopted validated through the redocking of nortriptyline in the DAT binding site, as describe elsewhere (Halperin et al 2002;Mohammad et al 2008), which was employed to obtain the molecular structures of dopamine, 6-OHDA, pquinone and DATi (DATi = 3α-bis-4-fluorophenyl-methoxytropane) (Tocris ® , cat.…”

The interface of protein-protein complexes: Analysis of contacts and prediction of interactions

“…The structures of the complex are revealed only at the time of the evaluation [75,76]. Docking procedures start from the atomic coordinates of the two interacting proteins, generate putative complexes, and give them a score [77]. In principle, there are computational methods such as molecular dynamics (MD) simulations available that can treat both binding partners as fully flexible.…”

Design and in Silico Construction of New Efficient Antibodies Against Gastric Tumor-associated Antigens Towards Introducing Combined Strategy for Vaccine Tumor Therapy

“…During the docking process, the scoring function rewarded the positive interactions between the receptor (antibody) and the ligand (antigen) while penalized the negative interactions. Assuming that the suitable and accurate biological complexes have the lowest energy, the calculation of energy levels can then be used to predict the future biological activity and potency of a biomolecule [14]. Consequently, the docking algorithm was used to calculate the energy levels within the antibody-antigen complex at interacting points, based on electrostatic and shape parameters via different statuses of their interactions.…”