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. In addition, 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 paper provides an overview of the program as it exists today with an emphasis on developments since the publication of the original CHARMM paper in 1983.

The self-consistent-charge density-functional tight-binding method (SCC-DFTB) is an approximate quantum chemical method derived from density functional theory (DFT) based on a second-order expansion of the DFT total energy around a reference density. In the present study we combine earlier extensions and improve them consistently with, first, an improved Coulomb interaction between atomic partial charges, and second, the complete third-order expansion of the DFT total energy. These modifications lead us to the next generation of the DFTB methodology called DFTB3, which substantially improves the description of charged systems containing elements C, H, N, O, and P, especially regarding hydrogen binding energies and proton affinities. As a result, DFTB3 is particularly applicable to biomolecular systems. Remaining challenges and possible solutions are also briefly discussed.

A quantum mechanical/molecular mechanical (QM/MM) approach based on an approximate density functional theory, the so-called self-consistent charge density functional tight binding (SCC-DFTB) method, has been implemented in the CHARMM program and tested on a number of systems of biological interest. In the gas phase, SCC-DFTB gives reliable energetics for models of the triosephosphate isomerase (TIM) catalyzed reactions. The rms errors in the energetics compared to B3LYP/6-31+G(d,p) are about 2−4 kcal/mol; this is to be contrasted with AM1, where the corresponding errors are 9−11 kcal/mol. The method also gives accurate vibrational frequencies. For the TIM reactions in the presence of the enzyme, the overall SCC-DFTB/CHARMM results are in somewhat worse agreement with the B3LYP/6-31+G(d,p)/CHARMM values; the rms error in the energies is 5.4 kcal/mol. Single-point B3LYP/CHARMM energies at the SCC-DFTB/CHARMM optimized structures were found to be very similar to the full B3LYP/CHARMM values. The relative stabilities of the αR and 310 conformations of penta- and octaalanine peptides were studied with minimization and molecular dynamics simulations in vacuum and in solution. Although CHARMM and SCC-DFTB give qualitative different results in the gas phase (the latter is in approximate agreement with previous B3LYP calculations), similar behavior was found in aqueous solution simulations with CHARMM and SCC-DFTB/CHARMM. The 310 conformation was not found to be stable, and converted to the αR form in about 15 ps. The αR conformation was stable in the simulation with both SCC-DFTB/CHARMM and CHARMM. The i,i+3 CO···HN distances in the αR conformation were shorter with the SCC-DFTB method (2.58 Å) than with CHARMM (3.13 Å). With SCC-DFTB/CHARMM, significant populations with i,i+3 CO···HN distances near 2.25 Å, particularly for the residues at the termini, were found. This can be related to the conclusion from NMR spectroscopy that the 310 configuration contributes for alanine-rich peptides, especially at the termini.