This section of the tutorial provides introductory information and some brief background necessary to comprehend the rest of the document.
About this tutorial
Welcome to charmmtutorial.org! This document is designed to teach newcomers the basics of setting up and running molecular simulations using the molecular simulation program CHARMM. It has been written in conjunction with the CHARMMing web portal. CHARMMing is a tool that provides a user-friendly interface for the preparation, submission, monitoring, and visualization of molecular simulations (i.e., energy minimization, solvation, and dynamics). The goal of this tutorial is to teach what is going on "behind the scenes" of the scripts that CHARMMing generates. This will help bridge the gap between using scripts developed by others and writing new CHARMM scripts to perform tasks. This tutorial is aimed at readers with some knowledge of molecular simulation (even if it's only classroom based or derived from using graphical tools such as CHARMMing), who have basic competency with the underlying physics, and who wish to use CHARMM to run a biomolecular simulation and analyze the resulting data.
These readers will primarily be advanced undergraduate or beginning graduate students. It does not aim to teach molecular simulation per se, but it does give background when needed to understand the examples with appropriate references given. The reader is not expected to know much about the practical details of simulation, but the basic principles of physical and biological chemistry are assumed to be known. To be specific, the reader is expected to know basic facts about:
Assumed biochemistry background
- Biopolymers (e.g. proteins, carbohydrates, and nucleic acid chains) and their constituent subunits (amino acids, monosaccharides, and individual nucleic acids)
- Sources of structural data (e.g. the Protein Data Bank, Cambridge Structural Database).
Assumed physics / physical chemistry background
- Atomic structure, ionic and covalent bonds, bond energy
- The relationship of atomic structure to system energy
- Nonbonded forces, such as electrostatics and van der Waals interactions
- Some statistical mechanics, e.g., the reader should have some familiarity with the basic ensembles (in particular micro-canonical and canonical ensemble), know about relationships between macroscopic and microscopic properties (e.g., temperature and average kinetic energy), and have heard about the ergodic theorem.
Assumed computer background
This tutorial assumes that you have login ability to a Unix machine (this includes MacOS X). We further assume that CHARMM is already installed on this machine and you know the command to invoke it. If you just received the CHARMM distribution and need help installing it, here are some installation instructions.
Since CHARMM is a command line program, you need some familiarity with the Unix shell (the Unix command line), even on MacOS X! You should be able to navigate the directory hierarchy, copy and move files, and know how to use a text editor. At the time of writing this tutorial, one good Introduction to the Unix command line can be found here; should this link be broken google for something like "introduction to the unix command line".
Suggested reading list
This list of texts is not definitive, but books that the authors have found useful.
Material about properties of amino acids and nucleic acids, as well as the structure of proteins, DNA and RNA in, e.g.,
- Phillips, Kondev, and Theriot. Physical Biology of the Cell. Garland Science. ISBN 0815341636
- Elliott & Elliott. Biochemistry and Molecular Biology. Oxford University Press. ISBN 0199226717
- Berg, Tymoczko and Stryer. Biochemistry. W.H. Freeman & Comp. ISBN 0716787245
and similar tomes.
Some general texts on physical chemistry contain quite good introductions to statistical mechanics/thermodynamics. In addition:
- Hill. An Introduction to Statistical Thermodynamics. Dover Publications. ISBN 0486652424
- Dill and Bromberg. Molecular Driving Forces: Statistical Thermodynamics in Chemistry & Biology. Garland Science. ISBN 0815320515
- Chandler. Introduction to Modern Statistical Mechanics. Oxford University Press. ISBN 0195042778
- Allen and Tildsley. Computer Simulations of Liquids. Oxford University Press. ISBN 0198556454
- Becker, MacKerrell, Roux, and Wanatabe (ed.). Computational Biochemistry and Biophysics, CRC Press. ISBN 082470455X.
- Leach. Molecular Modeling: Principles and Applications. Prentice Hall. ISBN 0582382106
- Smit and Frenkel. Understanding Molecular Simulation. Academic Press. ISBN 0122673514
Unix computing and utilities
- Robbins. UNIX In a Nutshell. O'Reilly Media Inc. ISBN 0596100299
About the molecular simulation field
Molecular simulations are performed for a wide variety of purposes. Often, they elucidate how subtle microscopic changes, such as the hydration of a protein interior, affect larger scale processes such as the folding of that protein. Molecular simulation is used across a breadth of disciplines in both organic and inorganic chemistry, however CHARMM, and therefore this tutorial, concentrates mainly on the study of systems of biological interest. Biomolecular simulations can provide insight into reactions that may be difficult to observe experimentally either due to the small size of the compounds involved or the rapid time scale of the event. A variety of techniques can be employed, from simple energy evaluations that can be performed with relatively few operations to long running molecular dynamics or monte carlo simulations using a complex system set up that can take months of computer time. The exact tools used will depend on the type of questions that the simulation (or group of simulations) is expected to answer. The end goal is to provide insight into the physical nature of a system.
Simulations may be performed at different levels of theory, depending on their goal. Perhaps the most familiar level is the classical all-atom representation of the system where interactions are modeled without using quantum mechanics. Higher levels than this directly employ the quantum mechanical properties of the atoms (they are used indirectly even in classical simulations as force fields are often parametrized from quantum mechanical data). Lower levels than the classical all-atom generally use coarse-graining, i.e. multiple atoms are grouped together into a single point mass. In general, higher levels of theory yield more accurate results, but at the cost of computer time.
As computer power expands, so too does the range of questions that can be answered by simulation. Currently modelers are able to simulate tens to hundreds of thousands of atoms over a time scale of tens to hundreds of nanoseconds at the classical all atom level of theory. Recent simulations of microsecond length simulations of complex systems have recently been reported. As important biological processes such as protein folding take place on the order of microseconds, this is an important development. The increase in computer power predicted (indirectly) by Moore's Law is expected to continue for at least the next decade. Therefore, many previously intractable problems should be solvable in the near future.
CHARMM (Chemistry at HARvard Molecular Mechanics) is a highly versatile and widely used molecular simulation program. It has been developed with a primary focus on molecules of biological interest, including proteins, peptides, lipids, nucleic acids, carbohydrates, and small molecule ligands, as they occur in solution, crystals, and membrane environments. The CHARMM program has been produced over the last thirty years by a vast team of developers lead by Martin Karplus's group at Harvard University. The program is distributed to academic research groups for a nominal fee; a commercial version is distributed by Accelrys.Information on acquiring CHARMM may be found on the CHARMM development project home page at www.charmm.org.
The most up to date reference for CHARMM is a 2009 article in the Journal of Computational Chemistry. (BR Brooks et al. CHARMM: The biomolecular simulation program. J Comp. Chem. (30)10 2009.)
Basic Information on running CHARMM
CHARMM is a command line program that runs on UNIX and UNIX-like systems (this is why, in the prerequisites section, we wanted you to have access to such a machine). Graphics are available (however they are not covered in this tutorial), but all interaction is done via text commands. Although CHARMM may be used interactively, most use is done via pre-written scripts (i.e. lists of commands that CHARMM executes). The following portion of the tutorial provides the basic information needed to use CHARMM's (powerful) scripting language effectively.
CHARMM can produce a number of files that may be input into third party programs for visualization or analysis (e.g., VMD includes the capability to read CHARMM coordinate and trajectory files). In general, this tutorial does not deal with these third party programs. However, here is a quick example of how to visualize CHARMM coordinate files with VMD: (vmd -psf structure.psf -cor structure.crd)
The best source of basic information about CHARMM and its capabilities are the aforementioned journal article and the resources given in the following subsection.
Sources of Further Information
- The CHARMM Web site http://www.charmm.org
- Information on acquiring CHARMM http://www.charmm.org/html/package/license.html
- Documentation http://www.charmm.org/documentation/current/index.html
- Discussion forums (where you can ask for help) http://www.charmm.org/ubbthreads
- Parameter files for CHARMM force fields http://mackerell.umaryland.edu/CHARMM_ff_params.html
- MD workshop at PSC http://www.psc.edu/general/software/packages/charmm/tutorial/index.php