PaCS-Toolkit: Optimized Software Utilities for Parallel Cascade Selection Molecular Dynamics (PaCS-MD) Simulations and Subsequent Analyses

Abstract

Parallel cascade selection molecular dynamics (PaCS-MD) is an enhanced conformational sampling method conducted as a "repetition of time leaps in parallel worlds", comprising cycles of multiple molecular dynamics (MD) simulations performed in parallel and selection of the initial structures of MDs for the next cycle. We developed PaCS-Toolkit, an optimized software utility enabling the use of different MD software and trajectory analysis tools to facilitate the execution of the PaCS-MD simulation and analyze the obtained trajectories, including the preparation for the subsequent construction of the Markov state model. PaCS-Toolkit is coded with Python, is compatible with various computing environments, and allows for easy customization by editing the configuration file and specifying the MD software and analysis tools to be used. We present the software design of PaCS-Toolkit and demonstrate applications of PaCS-MD variations: original targeted PaCS-MD to peptide folding; rmsdPaCS-MD to protein domain motion; and dissociation PaCS-MD to ligand dissociation from adenosine A_2A receptor.

Figure 1

Schematic illustration of how PaCS-MD trajectories evolve during the cycles, shown as projections onto the space spanned by the direction of the selection feature and other directions for the case of n_rep = 3. The circled numbers represent cycle numbers and are marked with the positions of the initial structures of each cycle.

Figure 2

Example of the configuration file, input.toml for dPaCS-MD conducted with GROMACS. Major keywords explained in the text are shown in blue.

Figure 3

Results of t-PaCS-MD/MSM on chignolin. (A) The native structure of chignolin (the top image. model 1 of 1UAO(65)) and four unfolded starting structures for t-PaCS-MD (the bottom image. green, yellow, orange, and magenta) best-fitted to residues 5 and 6 of the native structure are shown transparently. The images in Figures 1–3 were created by VMD unless otherwise specified. (B) Backbone RMSD (the selection feature) as a function of n_cyc during t-PaCS-MD. The horizontal lines show 0.1 and 0.05 nm. (C) Projections of folding pathways mapped onto the space spanned by the distances of HB1 and HB2. Representative pathways are selected from each trial and are shown in different colors. The square symbols indicate the positions of the initial structures, and the open triangle represents the native structure. (D) The free energy landscape of chignolin folding mapped onto the HB1–HB2 distance space.

Figure 4

Results of rmsdPaCS-MD/MSM on the Nsp15 monomer. (A) Backbone RMSD as a function of n_cyc during rmsdPaCS-MD for each trial. RMSDs for the whole molecule (the selection feature) and the N-term (blue), Mid (red), and C-domains (gray) are shown. The error bars represent the standard deviations between the replicas. (B) The monomer structure in the apo hexamer (cartoon representation) and examples of conformations generated by the rmsdPaCS-MD (thin tube representations) after best-fitting the C-term domain. The last snapshots of all of the trials from the first replica at n_cyc = 50 are shown. (C) The free energy profile as a function of d_com between the N- and C-term domains. The vertical line shows the d_com of the apo hexamer.

Figure 5

Results of dPaCS-MD/MSM on the A_2AR/LUF5833 complex. (A) A side view of the simulated system containing A_2AR (magenta), LUF5833 (spheres), the membrane region (white), water (blue), K⁺ (purple spheres), and Cl^– (cyan spheres). The image was created using ChimeraX.⁻ The chemical structure of LUF5833 is shown in the inset. (B) The intercenter-of-mass distance d_com (the selection feature) as a function of n_cyc during dPaCS-MD. (C) The dissociation pathways of LUF5833 from A_2AR (white cartoon model). The center of mass positions of LUF5833 along the dissociation pathways are shown as spheres in path-dependent colors. (D) The potential of mean force (PMF) as a function of d_com. The thick black line represents the average PMF and the dotted lines show individual PMFs from each trial.