CHARMM‐GUI Drude prepper for molecular dynamics simulation using the classical Drude polarizable force field

Abstract

Explicit treatment of electronic polarizability in empirical force fields (FFs) represents an extension over a traditional additive or pairwise FF and provides a more realistic model of the variations in electronic structure in condensed phase, macromolecular simulations. To facilitate utilization of the polarizable FF based on the classical Drude oscillator model, Drude Prepper has been developed in CHARMM‐GUI. Drude Prepper ingests additive CHARMM protein structures file (PSF) and pre‐equilibrated coordinates in CHARMM, PDB, or NAMD format, from which the molecular components of the system are identified. These include all residues and patches connecting those residues along with water, ions, and other solute molecules. This information is then used to construct the Drude FF‐based PSF using molecular generation capabilities in CHARMM, followed by minimization and equilibration. In addition, inputs are generated for molecular dynamics (MD) simulations using CHARMM, GROMACS, NAMD, and OpenMM. Validation of the Drude Prepper protocol and inputs is performed through conversion and MD simulations of various heterogeneous systems that include proteins, nucleic acids, lipids, polysaccharides, and atomic ions using the aforementioned simulation packages. Stable simulations are obtained in all studied systems, including 5 μs simulation of ubiquitin, verifying the integrity of the generated Drude PSFs. In addition, the ability of the Drude FF to model variations in electronic structure is shown through dipole moment analysis in selected systems. The capabilities and availability of Drude Prepper in CHARMM‐GUI is anticipated to greatly facilitate the application of the Drude FF to a range of condensed phase, macromolecular systems.

Does the inclusion of electronic polarisability lead to a better modelling of peptide aggregation?

“…Even though we assigned this as a b-strand as the Ab 16-22 peptide adopts a mostly extended random coil structure, there is no b-sheet present in the monomer. 52 The CD spectrum of Ab 16-22 is devoid of a-helical traces, also during the aggregation process, 8 which renders the C-Drude model of Ab [16][17][18][19][20][21][22] as less accurate than that of C36m. The results of Bera et al further show that the complete transition from random coil to b-sheet is a slow process, taking hours, 8 which suggests that C36m may overestimate the amyloid aggregation speed by predicting Ab 16-22 to almost directly develop into an antiparallel b-sheet.…”

“…The initial structures were processed for the C-Drude simulations using CHARMM-GUI Drude Prepper. 20 Each monomer and dimer structure was solvated and the resulting systems were energy-minimised for 5000 steps using the steepest descent method, followed by equilibration MD simulations for 100 ps using a time step of 0.5 fs at a pressure of 1 bar and a temperature of 310 K, which were regulated via a Monte Carlo barostat and a Langevin thermostat, respectively. During the equilibration phase, the peptide-backbone and side-chain atoms were restrained using harmonic potentials with spring constants of 400.0 kJ mol −1 nm 2 and 40.0 kJ mol −1 nm 2 , respectively.…”

“…We now turn our attention to the dimerisation of Ab [16][17][18][19][20][21][22] . In our previous study we analysed this process in detail based on a 10 ms MD simulation that employed a variant of the C36m force eld that employs increased protein-water interactions.…”

“…1 However, the results of biomolecular MD simulations depend sensitively on the force eld used to model the system in question. 2 We and others demonstrated this problem for both monomeric Ab 3 and amyloid aggregation where the fragment Ab [16][17][18][19][20][21][22] was used as a test case. [4][5][6] This peptide has the sequence KLVFFAE, containing the hydrophobic residues 17-21 which play a major role in the aggregation of Ab, 7,8 and it is known to aggregate into amyloid brils with an antiparallel b-sheet architecture.…”

Relative binding free energy calculations with transformato: A molecular dynamics engine-independent tool

“…E.g., with OpenMM, we can use the CGenFF parameters that place lone-pairs on the halogens ( Gutiérrez et al, 2016 ) 2 . Further extending transformato to the Drude polarizable force field, given the existing support in OpenMM ( Huang et al, 2018 ) and CHARMM-GUI ( Kognole et al, 2021 ), should be straightforward.…”