Quantum Fragment Based ab Initio Molecular Dynamics for Proteins

Abstract

Developing ab initio molecular dynamics (AIMD) methods for practical application in protein dynamics is of significant interest. Due to the large size of biomolecules, applying standard quantum chemical methods to compute energies for dynamic simulation is computationally prohibitive. In this work, a fragment based ab initio molecular dynamics approach is presented for practical application in protein dynamics study. In this approach, the energy and forces of the protein are calculated by a recently developed electrostatically embedded generalized molecular fractionation with conjugate caps (EE-GMFCC) method. For simulation in explicit solvent, mechanical embedding is introduced to treat protein interaction with explicit water molecules. This AIMD approach has been applied to MD simulations of a small benchmark protein Trpcage (with 20 residues and 304 atoms) in both the gas phase and in solution. Comparison to the simulation result using the AMBER force field shows that the AIMD gives a more stable protein structure in the simulation, indicating that quantum chemical energy is more reliable. Importantly, the present fragment-based AIMD simulation captures quantum effects including electrostatic polarization and charge transfer that are missing in standard classical MD simulations. The current approach is linear-scaling, trivially parallel, and applicable to performing the AIMD simulation of proteins with a large size.

Quantum mechanical force fields for condensed phase molecular simulations

“…144–146 Ideas have been proposed for nonempirically incorporating short-range nonbond repulsions by introducing inter-fragment orthogonality restraints into X-Pol 147 but practical applications of those ideas have not yet been explored.…”

“…Another approach to avoid using Ewald’s method with ab initio Hamiltonians include the Reaction Field method; 186,187 however, the predominant choice continues to be the use of real-space electrostatic truncation. 127,146,188–194 …”

“…Whereas LSQMs have been useful for many problems, the efficiency, and in some cases the accuracy of QMFFs have the potential to considerably extend the range of applications, particularly in condensed phase molecular simulations. Fragment-based methods have seen recent use within molecular dynamics simulations, 59,60,109,146,196,197 and to explore the importance of many-body interactions. 53,198 The FMO and mDC methods have been used in drug docking applications of cyclin-dependent kinase 2 inhibitor, 59,199 and to perform PMF profiles of chemical reactions.…”

Systematic Error Estimation for Chemical Reaction Energies

“…Electronic structures exhibited by transition-metal complexes are so diverse that it is very difficult to represent them in an unbiased benchmark set. If accurate reference data for the chemical system of interest were available, one could not even assume the error of a DFT result to be constant among homologous molecules [23,27]. In a recent study [23], we showed that popular density functionals struggle to reproduce experimental ligand dissociation energies of large organometallic transition-metal complexes in our WCCR10 reference set.…”

Ambient-Potential Composite Ewald Method for ab Initio Quantum Mechanical/Molecular Mechanical Molecular Dynamics Simulation

“…69,70,72–76 However, applications of ab initio QM/MM often still forego the use Ewald summations, preferring instead to model the long-range electrostatic with a reaction field method 77,78 or perform real-space electrostatic truncation, shifting, or smoothing. 52–54,79–84 Recent work has advocated a 22 Å real-space switched electrostatic cutoff method using the minimum image convention. 85 Regrettably we’ve noticed that many authors have failed to report the size of the QM/MM nonbond cutoff that they’ve used, and other details defining how the electrostatics were performed.…”