The combination of quantum mechanics and molecular mechanics (QM/MM), since the seminal work Warshel and Levitt (J. Mol. Biol. 103, 227 (1976)), accompanied by the increasing computational power of modern parallel and vector-parallel platforms, has been a real breakthrough in the simulations of realistic large systems, with special emphasis for biomolecular structures and related reactions (for a review, see for instance H. M. Senn and W. Thiel Angew. Chem. Int. Ed. 48, 1198 (2009)). This has made possible to start an entirely new branch of biological chemistry, which, beside the traditional in vivo and in vitro experiments, offers now the possibility of performing with great accuracy virtual experiments on computers. This has even given rise to a new terminology, in silico, coined in 1989 by the Mexican mathematician Pedro Miramontes to indicate computer simulations of biological experiments.
However, the generality and variety of QM/MM approaches makes difficult their specific choice and practical use by students and young researchers facing this field for the first time. Moreover, the availability of computer codes freely downloadable from the web hides a severe drawback. Users tend to use these packages as a sort of “black box” without really knowing what kind of calculations a particular code does (or does not) and which is the theory behind, not to mention the actual strength and crucial limitations of a particular QM/MM approach. The scope of the present tutorial will be the presentation of the main QM/MM approaches for simulating biomolecular systems. Special emphasis will be given to their advantages and disadvantages, practical applications and new advanced techniques exploring the terrain beyond the simple static relaxations and molecular dynamics simulations of proteins and nucleic acids. The main goal will be to provide to neophytes a solid background to enable them to simulate complex systems of biological, medical and environmental relevance. The tutorial is organized with theoretical lessons and examples of successful (and unsuccessful) simulations, as well as with practical exercises, planned for the afternoon sessions. An initial set (two half days) of theoretical lessons has been planned to build-up a necessary minimal background enabling students to start QM/MM simulations autonomally. An important point, unfortunately still unclear to beginners and unexperienced users, is the fact that the chemistry of the biochemical system and the specific process that one plans to study crucially determine the QM approach, the type of QM/MM interface and the majority of the parameters (and their tuning) involved in the coupling of a classical force field with a quantum mechanical approach.
One of the major tasks of this tutorial is to make neophytes able to select a specific, small QM region in a large biomolecular system “as provided” by experiments and Protein Data Bank (http://www.pdb.org/) that will be handled at the QM level. This choice is always somehow arbitrary and dependent on the quantum process (chemical reactions, charge transfers, etc.) one wants to focus on. A second, equally important task, is the problem of the time scale. QM/MM simulations have in fact the same picoseconds time-scale problem affecting full quantum calculations; methods enabling the enhance of the sampling of rare events (activated processes), such as metadynamics, Blue Moon etc. represent a viable tool to overcome this problem, hence to expand simulations not only with respect to the size of the system but also with respect to the time.