CECAM

Hybrid Quantum Mechanics / Molecular Mechanics (QM/MM) Approaches to Biochemistry (and beyond)

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.

References

1) H. M. Senn and W. Thiel, Angew. Chem. Int. Ed. 48, 1198 (2009)
2) A. Warshel and M. Levitt, J. Mol. Biol. 103, 227 (1976)
3) M. J. Field, P. A. Bash and M. Karplus, J. Comput. Chem. 11, 700 (1990)
4) “Combined Quantum Mechanical and Molecular Mechanical Methods” ACS Symp. Ser. Vol. 712, ed. by J. Gao and M. A. Thompson, American Chemical Society, Washington, 1998
5) “Encyclopedia of Computational Chemistry”, Vol. 1-4, ed. by P. v. Schleyer, Wiley, Chirchester, 1998
6) P. Sherwood, in “Modern Methods and Algorithms of Quantum Chemistry” NIC Ser. Vol. 1, John von Neumann Institute of Computing, Juelich 2000, pp. 257-277
7) P. Amara and M. J. Field in “Computational Molecular Biology” Vol. 8, ed. by J. Leszczynski, Elsevier, Amsterdam, 1999
8) M. Echinger, P. Tavan, J. Hutter, and M. Parrinello, J. Chem. Phys. 110, 10452 (1999)
9) A. Laio, J. VandeVondele, and U.Rothlisberger, J. Chem. Phys. 116, 6941 (2002).
10) A. Laio, J. VandeVondele, and U.Rothlisberger, J. Phys. Chem. B 106, 7300,(2002)
11) U. Roethlisberger, P. Carloni, Lect. Notes Phys. 704, 437 (2006)
12) P. D. Lyne and O. A. Walsh in “Computational Biochemistry and Biophysics”, ed. by O. M. Becker and M. Watanabe, Dekker, New York, 2001, pp. 221-236
13) A. J. Mulholland in “Theoretical Biochemistry: Processes and Properties of Biological Systems”, Theor. Comput. Chem. vol. 9, ed. by L. A. Eriksson, Elsevier, Amsterdam, 2001, pp. 597-653
14) W. Andreoni, Perspectives in Drug Discovery and Design 9, 161 (1998)
15) M. Dal Peraro, P. Ruggerone, S. Raugei, F. L. Gervasio, and P. Carloni, Curr. Opinion Struct. Biol. 17, 149 (2007)
16) S. C. Rossle and I. Frank, Frontiers in Biosci. 14, 4862 (2009)
17) P. Vidossich, G. Florin, M. Alfonso-Prieto, E. Derat, S. Shaik, and C. Rovira, J. Phys. Chem. B 114, 5161 (2010)
18) M. E. Moret, E. Tapavicza, L. Guidoni, U. F. Rohrig, M. Sulpizi, I. Tavernelli, and U. Röthlisberger, Chimia 59, 493 (2005)
19) M. Boero, T. Ikeda, E. Ito, and K. Terakura, J. Am. Chem. Soc. 128, 16798 (2006)
20) M. Boero “Reactive Simulations for Biochemical Processes, in Atomic-Scale Modeling of Nanosystems and Nanostructured Materials”, Lecture Notes Phys. 795, pag. 81-98, Springer, Berlin Heidelberg 2010. ISBN 978-3-642-04650-6

Denmark

Per Jr. GREISEN (Technical University of Denmark)

Finland

Oana CRAMARIUC (Tampere University of Technology)

France

Ari Paavo SEITSONEN (Ecole Normale Supérieure)
Raghvendra P. SINGH (IEMN University of Lille 1)

Germany

Sebastian BRAUN (Ruhr-Universität Bochum)

Ireland

Eva RIVERA (University College Dublin)

Italy

Emanuele COCCIA (Department of Physical and Chemical Sciences, University of L’Aquila)
Duvan FRANCO (International School for Advanced Studies)
Claudio GRECO (University of Milano-Bicocca)
Giulia PALERMO (Italian Institute of Technology, Genova)
Francesco RAGONE (Università degli Studi di Salerno)
Federica TRUDU (National Research Council (CNR))

The Netherlands

Murat KILIÇ (University of Amsterdam)

Poland

Katarzyna KULCZYCKA-MIERZEJEWSKA (University of Warsaw)

Spain

Rodrigo CASASNOVAS (University of the Balearic Islands)
Elena FORMOSO (Donostia Internatioal Physics Centers)
Javier IGLESIAS FERNáNDEZ (Barcelona Science Park)
Alejandro PEREZ PAZ (University of the Basque Country UPV/EHU)
Antonio RODRíGUEZ-FORTEA (University Rovira-Virgili )

Sweden

Francesca MOCCI ( Stockholm University)

Switzerland

Christophe BOVIGNY (Swiss Federal Institute of Technology Lausanne)
Pablo CAMPOMANES (University of Fribourg)
Yun DING (ETH Zurich and University of Lugano)
Grégoire GALLET (Swiss Federal Institute of Technology Lausanne (EPFL))
Roberto GASPARI (Swiss Federal Laboratories for Materials, Science and Technology (EMPA), Dübendorf)
Ciro Achille GUIDO (Swiss Federal Institute of Technology Lausanne (EPFL))
Ali HASSANALI (ETH Zurich and USI Lugano)
Teodoro LAINO (IBM Research – Zurich)

United Kingdom

Marian BREUER (University College London)
Greg LEVER (University of Cambridge)

Monday February 14th 2011 – Day 1
 

14:00 to 14:10 – Registration
14:10 to 15:00 – Carme Rovira 
Why using a QM/MM approach. How to set-up a QM/MM system: From pristine crystallographic coordinates to the set-up for dynamical simulations. Part I
15:00 to 15:50 – Mauro Boero 
Practical aspects: QM size, initial structure (classical equilibration), Computational needs.
15:50 to 16:10 – Coffee Break
16:10 to 17:00 – Mauro Boero 
Partitioning the system: Hamiltonian and calculation of forces.
17:00 to 17:50 – Carme Rovira 
Why using a QM/MM approach. How to set-up a QM/MM system: From pristine crystallographic coordinates to the set-up for dynamical simulations. Part II. Examples 1.
Tuesday February 15th 2011 – Day 2
 

09:00 to 09:50 – Mauro Boero 
QM/MM border: Link Atoms (LA), Frontier Orbitals (FO), Optimized Effective Core Potentials (OECP), scaled-position link atom method (SPLAM)
09:50 to 10:50 – Ivano Tavernelli 
Interactions between the QM and MM subsystems: Rescaled Electrostatic Potential (RESP) scheme, Polarized-Boundary Redistributed Charge (PBRC) and dipole (PBRCD)
10:50 to 11:10 – Coffee Break
11:10 to 12:00 – Teodoro Laino 
Real space multigrid QM/MM implementation.
12:00 to 12:45 – Teodoro Laino 
Examples of (successful and unsuccessful) Applications 2
12:45 to 14:00 – Lunch
14:00 to 18:00 – Exercises
Wednesday February 16th 2011 – Day 3
 

09:00 to 09:50 – Mauro Boero 
(N,V,E) and (N,V,T) Molecular dynamics within QM/MM: crucial parameters controlling the dynamics.
09:50 to 10:50 – Teodoro Laino 
Efficient Treatment of Long-Range interactions in a QM/MM scheme.
10:50 to 11:10 – Coffee Break
11:10 to 12:00 – Ari Paavo Seitsonen 
Numerical integration schemes for the equations of motion, constants of motion, control of stability, accuracy.
12:00 to 12:45 – Carme Rovira 
Examples of (successful and unsuccessful) Applications 3
12:45 to 14:00 – Lunch
14:00 to 18:00 – Exercises
19:00 to 21:00 – Dinner
Thursday February 17th 2011 – Day 4
 

09:00 to 09:50 – Ivano Tavernelli 
Advanced techniques: Combining QM/MM with TD-DFT (1)
09:50 to 10:50 – Carme Rovira 
Examples of (successful and unsuccessful) Applications 4
10:50 to 11:10 – Coffee Break
11:10 to 12:00 – Ivano Tavernelli 
Advanced techniques: Combining QM/MM with TD-DFT (part 2)
12:00 to 12:45 – Mauro Boero 
Advanced techniques: Combining QM/MM with Metadynamics/Blue Moon Ensemble
12:45 to 14:00 – Lunch
14:00 to 18:00 – Exercises
Friday February 18th 2011 – Day 5
 

09:00 to 09:50 – Mauro Boero 
Examples of (successful and unsuccessful) Applications 5
09:50 to 10:50 – Carme Rovira 
Examples of (successful and unsuccessful) Applications 6
10:50 to 11:10 – Coffee Break
11:10 to 12:30 – Poster Session
12:30 to 12:45 – Closing Word
12:45 to 14:00 – Lunch
14:00 to 18:00 – Exercises