A QM/MM implementation of the self-consistent charge density functional tight binding (SCC-DFTB) method

A quantum mechanical/molecular mechanical (QM/MM) approach based on an appr oximate density functional theory, the so-called self-consistent charge den sity functional tight binding (SCC-DFTB) method, has been implemented in th e 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 trio sephosphate isomerase (TIM) catalyzed reactions. The rms errors in the ener getics 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 i n the presence of the enzyme, the overall SCC-DFTB/CHARMM results are in so mewhat worse agreement with the B3LYP/6-31+G(d,p)/CHARMM values; the rms er ror in the energies is 5.3 kcal/mol. Single-point B3LYP/CHARMM energies at the SCC-DFTB/CHARMM optimized structures were found to be very similar to t he full B3LYP/CHARMM values. The relative stabilities of the alpha (R) and 3(10) conformations of penta- and octaalanine peptides were studied with mi nimization and molecular dynamics simulations in vacuum and in solution. Al though CHARMM and SCC-DFTB give qualitative different results in the gas ph ase (the latter is in approximate agreement with previous B3LYP calculation s), similar behavior was found in aqueous solution simulations with CHARMM and SCC-DFTB/CHARMM. The 310 conformation was not found to be stable, and c onverted to the alpha (R) form in about 15 ps. The cia conformation was sta ble in the simulation with both SCC-DFTB/CHARMM and CHARMM. The i,i+3 CO HN distances in the CIR conformation were shorter with the SCC-DFTB method (2 .58 Angstrom) than with CHARMM (3.13 Angstrom). With SCC-DFTB/CHARMM, signi ficant populations with i,i+3 CO.. HN distances near 2.25 Angstrom, particu larly for the residues at the termini, were found. This can be related to t he conclusion from NMR spectroscopy that the 310 configuration contributes for alanine rich peptides, especially at the termini.