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CHARMM (Chemistry at HARvard Molecular Mechanics) is a highly versatile and widely used molecular simulation program. It has been developed over the last three decades 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. For the study of such systems, the program provides a large suite of computational tools that include numerous conformational and path sampling methods, free energy estimators, molecular minimization, dynamics, and analysis techniques, and model-building capabilities. The CHARMM program is applicable to problems involving a much broader class of many-particle systems. Calculations with CHARMM can be performed using a number of different energy functions and models, from mixed quantum mechanical-molecular mechanical force fields, to all-atom classical potential energy functions with explicit solvent and various boundary conditions, to implicit solvent and membrane models. The program has been ported to numerous platforms in both serial and parallel architectures. This article provides an overview of the program as it exists today with an emphasis on developments since the publication of the original CHARMM article in 1983., (Copyright 2009 Wiley Periodicals, Inc.)

In a previous paper [Ghysels et al., J. Chem. Phys. 126, 224102 (2007)] the mobile block Hessian (MBH) approach was presented. The method was designed to accurately compute vibrational modes of partially optimized molecular structures. The key concept was the introduction of several blocks of atoms, which can move as rigid bodies with respect to a local, fully optimized subsystem. The choice of the blocks was restricted in the sense that none of them could be connected, and also linear blocks were not taken into consideration. In this paper an extended version of the MBH method is presented that is generally applicable and allows blocks to be adjoined by one or two common atoms. This extension to all possible block partitions of the molecule provides a structural flexibility varying from very rigid to extremely relaxed. The general MBH method is very well suited to study selected normal modes of large macromolecules (such as proteins and polymers) because the number of degrees of freedom can be greatly reduced while still keeping the essential motions of the molecular system. The reduction in the number of degrees of freedom due to the block linkages is imposed here directly using a constraint method, in contrast to restraint methods where stiff harmonic couplings are introduced to restrain the relative motion of the blocks. The computational cost of this constraint method is less than that of an implementation using a restraint method. This is illustrated for the alpha-helix conformation of an alanine-20-polypeptide.

This unit is the first in a series of four units covering the analysis of nucleic acid structure by molecular modeling. This unit provides an overview of computer simulation of nucleic acids. Topics include the static structure model, computational graphics and energy models, generation of an initial model, and characterization of the overall three-dimensional structure.

Molecular modeling and energy calculations have been used to study how delta-hemolysin and melittin helices may aggregate on membrane surfaces and insert through membranes to form channels. In these models adjacent antiparallel amphipathic helices form planar "raft" structures, in which one surface is hydrophobic and the other hydrophilic. Models of delta-hemolysin crystal structure were developed using these "rafts." These models are based on the unit cell constants and the crystal symmetry obtained from the preliminary crystal data. Energy calculations favor channel models of delta-hemolysin with six or eight monomers per channel.

Three-dimensional computer models for two segments of the C terminus of gp41, the transmembrane AIDS envelope protein, which may form amphipathic alpha-helices, have been generated using structure prediction techniques combined with energy minimization and molecular dynamics simulations. Regions gp41(772-790) and gp41(828-848) of the HXB2 strain of HIV-1 display extraordinarily high hydrophobic moment maxima as alpha-helices and when in an antiparallel conformation exhibit charge complementarity, implying that they may bind with each other and associate with the membrane. The feasibility of this hypothesis was tested in a series of computer simulations of these peptides, extended by several residues to include additional charge pairing. Beginning with a trial structure in the form of antiparallel alpha-helices of segments 770-794 and 824-856, systematic axial rotations and displacements were used to generate alternative initial states. Molecular dynamics simulations with alpha-helical torsional restraints yielded several approximately cylindrical dimeric structures highly stabilized by numerous salt links and other hydrogen bonds. This suggests that these two regions may fold back on each other in antiparallel fashion to form a loop in the tertiary structure over residues 770-856, with the loop closed by membrane-associated amphipathic alpha-helices with charged sides facing each other. We speculate that such structures could aggregate to form channels or otherwise destabilize the membrane, thereby contributing to the cytopathic effects of the gp120-gp41 complex.

The primary amino acid structure of the lysozyme-binding antibody, HyHEL-10, as determined by amino acid and nucleotide sequencing was utilized to construct a scale model of the Fv (variable region domain of immunoglobulin) using energy-minimized torsional angles of the McPC603 Fv as a prototype template. This model was in turn used as a template for generating a computer-built set of co-ordinates, which were subjected to a total of 600 steps of Adopted Basis Newton-Raphson energy minimizations using the program CHARMM. Only minimal shifts of the backbone (root-mean-square 0.76 A) were required to give an energetically stable structure with a favorable van der Waals' energy. Several notable features were evident from both the scale model and the energy-minimized computer model: (1) the shape of the antibody combining region is that of a very shallow concavity approximately 20 A X 25 A; (2) the concavity is acidic and non-hydrophobic and is bordered by hydrophobic segments; (3) the lower portion of the combining site is dominated by a cluster of tyrosine residues over the L3 and H2 areas; (4) a somatic mutation encoded by the J region of the heavy chain (JH) may contribute significantly to the complementarity of heavy chain H3 to the epitope on hen egg white lysozyme. In addition, the space-filling energy-minimized model revealed that residue 49L, a framework residue, was prominently exposed and accessible in the center of the combining-site concavity. The model suggests that variation in length of complementarity-determining regions may function not only to change directly the shape of the antibody combining site, but may also influence indirectly the nature of the antibody surface by changing the accessibility of residues not usually involved in antigen binding.