Metadynamics combined with auxiliary density functional and density functional tight-binding methods: alanine dipeptide as a case study

Abstract

Application of ab initio molecular dynamics to study free energy surfaces (FES) is still not commonly performed because of the extensive sampling required. Indeed, it generally necessitates computationally costly simulations of more than several hundreds of picoseconds. To achieve such studies, efficient density functional theory (DFT) formalisms, based on various levels of approximate computational schemes, have been developed, and provide a good alternative to commonly used DFT implementations. We report benchmark results on the conformational change FES of alanine dipeptide obtained with auxiliary density functional theory (ADFT) and second- and third-order density functional tight-binding (DFTB) methods coupled to metadynamics simulations. The influence of an explicit water solvent is also studied with DFTB, which was made possible by its lower computational cost compared to ADFT. Simulations lengths of 2.1 and 15 ns were achieved with ADFT and DFTB, respectively, in a reasonably short computational time. ADFT leads to a free energy difference (ΔF ) of ∼ -3 kcal mol between the two low energy conformers, C and C, which is lower by only 1.5 kcal mol than the ΔF computed with DFTB. The two minima in ADFT FES are separated by an energy barrier of 9 kcal mol, which is higher than the DFTB barriers by 2-4 kcal mol. Despite these small quantitative differences, the DFTB method reveals FES shapes, confor-mation geometries and energies of the stationary points in good agreement with these found with ADFT. This validates the promising applicability of DFTB to FES of reactions occurring in larger-size systems placed in complex environments.

Density-functional tight-binding: basic concepts and applications to molecules and clusters

“…Obviously, MD is also be used to follow the dynamical aspects of the system, for instance to simulate a reaction, collision and/or fragmentation (see section 4.7). A Car-Parrinello version of DFTB molecular dynamics was also implemented [176] as well as biased dynamics schemes like metadynamics [177][178][179]. Thermodynamical quantities can also be calculated.…”

Dcdftbmd: Divide‐and‐Conquer Density Functional Tight‐Binding Program for Huge‐System Quantum Mechanical Molecular Dynamics Simulations

“…The currently implemented CVs are geometric quantities and presented in Supporting Information. The applications of DFTB-based metadynamics are recently growing, [57,[124][125][126][127] yet their investigated system size has been less than a few hundreds of atoms. The combination with the DC method may be feasible to analyze large complex systems as demonstrated in simulation example section.…”

Molecular Simulations with in-deMon2k QM/MM, a Tutorial-Review

“…One possibility is the use of restraints on distances (or difference of distances), angles or dihedrals that allows the construction of the potential of mean force for studying chemical reactions or conformational rearrangements [62,63]. Another approach is the metadynamics (MetaD) [64,65] tool available via the PLUMED 2.x package [26], which has been plugged into deMon2k [27]. For this article our original implementation for gas phase MetaD simulations has been extended to hybrid QM/MM and QM/Onsager MetaD simulations.…”