Protein-ligand docking is currently an important tool in drug discovery efforts and an active area of research that has been the subject of important developments over the last decade. These are well portrayed in the rising number of available protein-ligand docking software programs, increasing level of sophistication of its most recent applications, and growing number of users. While starting by summarizing the key concepts in protein-ligand docking, this article presents an analysis of the evolution of this important field of research over the past decade. Particular attention is given to the massive range of alternatives, in terms of protein-ligand docking software programs currently available. The emerging trends in this field are the subject of special attention, while old established docking alternatives are critically revisited. Current challenges in the field of protein-ligand docking such as the treatment of protein flexibility, the presence of structural water molecules and its effect in docking, and the entropy of binding are dissected and discussed, trying to anticipate the next years in the field.

M-CSA (Mechanism and Catalytic Site Atlas) is a database of enzyme active sites and reaction mechanisms that can be accessed at www.ebi.ac.uk/thornton-srv/m-csa. Our objectives with M-CSA are to provide an open data resource for the community to browse known enzyme reaction mechanisms and catalytic sites, and to use the dataset to understand enzyme function and evolution. M-CSA results from the merging of two existing databases, MACiE (Mechanism, Annotation and Classification in Enzymes), a database of enzyme mechanisms, and CSA (Catalytic Site Atlas), a database of catalytic sites of enzymes. We are releasing M-CSA as a new website and underlying database architecture. At the moment, M-CSA contains 961 entries, 423 of these with detailed mechanism information, and 538 with information on the catalytic site residues only. In total, these cover 81% (195/241) of third level EC numbers with a PDB structure, and 30% (840/2793) of fourth level EC numbers with a PDB structure, out of 6028 in total. By searching for close homologues, we are able to extend M-CSA coverage of PDB and UniProtKB to 51 993 structures and to over five million sequences, respectively, of which about 40% and 30% have a conserved active site.

Quantum mechanics/molecular mechanics (QM/MM) methods offer a very appealing option for the computational study of enzymatic reaction mechanisms, by separating the problem into two parts that can be treated with different computational methods. Hence, in a QM/MM formalism, the part of the system in which catalysis actually occurs and that involves the active site, substrates and directly participating amino acid residues is treated at an adequate quantum mechanical level to describe the chemistry taking place. For the remaining of the enzyme, which does not participate directly in the reaction, but that typically involves a much larger number of atoms, molecular mechanics is employed, traditionally through the application of a biomolecular force field. When applied with care, QM/MM methods can be used with great advantage in comparing, at a structural and energetic level, different mechanistic proposals, discarding mechanistic alternatives and proposing new mechanistic pathways that are consistent with the available experimental data. With time, diverse flavors within the QM/MM methods have emerged, differing in a variety of technical and conceptual aspects. Hence present alternatives differ between additive and subtractive QM/MM schemes, the type of boundary schemes, and the way in which the electrostatic interactions between the two regions are accounted for. Also, single‐conformation QM/MM, multi‐PES approaches, and QM/MM Molecular Dynamics coexist today, each type with its own advantages and limitations. This review focuses on the application of QM/MM methods in the study of enzymatic reaction mechanisms, briefly presenting also the most important technical aspects involved in these calculations. Particular attention is dedicated to the application of the single‐conformation QM/MM, multi‐PES QM/MM studies, and QM/MM‐FEP methods and to the advantages and disadvantages of the different types of QM/MM. Recent breakthroughs are also introduced. A selection of hand‐picked examples is used to illustrate such features. WIREs Comput Mol Sci 2017, 7:e1281. doi: 10.1002/wcms.1281 This article is categorized under: Structure and Mechanism > Computational Biochemistry and Biophysics Structure and Mechanism > Reaction Mechanisms and Catalysis Electronic Structure Theory > Combined QM/MM Methods