Dataset of TopoTunnel

Overview This Zenodo record contains the processed experimental data used in the TopoTunnelMiner study. The collection includes processed tunnel-analysis outputs for LinB wild-type/open/close systems under conventional molecular dynamics (cMD) and Gaussian accelerated molecular dynamics (GaMD), CAVER configuration files, CYP3A4 data used for topology-stability evaluation, and residue-exclusion control experiments. Data Provenance: The CYP3A4 data were derived from the public MD study of Ackad et al. [1], whereas the LinB state datasets were based on the benchmark cMD/GaMD simulations reported by Mandal et al. [2]. Dataset Organization The dataset is organized by protein system, simulation protocol, and analysis purpose: Main LinB Experiments (wt, open, close): Processed outputs and selected structural inputs for LinB systems. Configuration Files (caver_config): CAVER parameter files used to generate tunnel results. CYP3A4 Data (CYP3A4): Input and processed data used for rigid-body stability evaluation. Archive-Level Description 1. Main LinB Experiments Archives: wt-cmd.rar, wt-gamd.rar, open-cmd.rar, open-gamd.rar, close-cmd.rar, close-gamd.rar (outputs); Linb-wt_cmd_run1_pdb_frames.rar, Linb-wt_GaMD_run1_frames.rar (inputs) These archives contain the main processed outputs and structural inputs for the LinB systems derived from the benchmark simulations of Mandal et al. [2]. Organization: Organized by conformational state (wt, open, close) and simulation protocol (cMD and GaMD). Processed Outputs: Each archive contains five independent run-level result folders (e.g., wt-cmd1-out to wt-cmd5-out). Each folder stores TopoTunnelMiner outputs, including a reference conformation file, an integrated path database, and residue-level statistical summaries. Structural Inputs: The wt_cmd_run1_pdb_frames.rar and wt_GaMD_run1_frames.rar archives provide the corresponding frame-level structural inputs for the first wild-type cMD and GaMD trajectories. Each contains 25,000 PDB snapshots, allowing users to reproduce the tunnel-computation stage prior to TopoTunnelMiner processing. 2. CAVER Configurations Archive: caver_config.rar Contains three plain-text CAVER configuration files used to document the exact settings for tunnel computation: CYP3A4_caver_config.txt: Used for the CYP3A4 stability experiment (Ackad et al. [1]). LinB_caver_config.txt: Used for the standard LinB analyses (Mandal et al. [2]). 3. CYP3A4 Topology-Stability Data Archive: CYP3A4.rar Derived from the MD ensemble reported by Ackad et al. [1], this archive contains: CYP3A4_full_Trajectory: 10,000 exported PDB snapshots (frame_*.pdb) representing the source structure pool. CYP3A4_500frames: The reduced dataset used in stability analysis, including aligned PDB frames, CAVER outputs, TopoTunnelMiner processed outputs, rigidly transformed PDB frames, transformed tunnel profiles, and the Python script (randomize_pdb_and_tunnels.py) used to generate random rigid-body perturbations. 4. Residue-Exclusion Controls Archives: wt-cmd1-ex176_272.rar and wt-gamd1-ex176_272.rar These archives validate the effect of residue removal on tunnel formation and residue-pair statistics in the LinB wild-type system (Mandal et al. [2]). 5. Energy-Based Matching Validation Archive: energy_experiment.rar This archive contains the structural path databases and tunnel-level CaverDock outputs used for the energy-based validation of constraint-based matching among the LinB WT, Open, and Closed variants. The deposited data link the structural tunnel representations generated by TopoTunnelMiner with the ligand-transport energy profiles derived from the LinB CaverDock dataset of Mandal et al. [2], using the CaverDock methodology described by Filipovic et al. [3]. The archive contains two top-level directories: - db/ contains nine TopoTunnelMiner output folders covering the P1B, P3, and ST tunnel families in the WT, Open, and Closed variants. Each folder contains a preprocessed_paths.db database, a representative protein structure, and residue-, residue-pair-, and residue-combination-level summaries. The databases store tunnel geometry, lining-residue associations, path-point coordinates, and topological anchor information used to construct the source sets and constraint-matched subsets. - energy/ contains the corresponding CaverDock v1.1 outputs, organized hierarchically by tunnel family, protein variant, and transported species. The archive covers three tunnel families (P1B, P3, and ST), three LinB variants (WT, Open, and Closed), and four transported species: 2-bromoethanol (BE), bromide ion (BR), 1,2-dibromoethane (DBE), and water (H2O). Each of the 36 family– variant–species combinations contains 100 tunnel-level result directories, yielding 3,600 tunnel–species cases in total. The deposited files include upper-bound energy profiles, transition-state barrier summaries, CaverDock configuration files, and the aligned tunnel and protein structures retained in the original calculations. These data support three analyses reported in the study: (i) the heterogeneous within-WT mixed-pool benchmark, (ii) the homogeneous within-family 50/50 split control, and (iii) the six directed cross-variant comparisons evaluated at (K=0.8), together with the (K=0.6)–1.0 parameter-sensitivity analysis. The archive provides the structural databases and source CaverDock outputs required for these analyses; the derived aggregate statistics and figures are reported in the manuscript and Supporting Information. References [1] Ackad, E. M.; Biggers, L.; Meister, M.; Kontoyianni, M. Equilibrium landscape of ingress/egress channels and gating residues of the Cytochrome P450 3A4. PLOS ONE 2024, 19(3), e0298424. https://doi.org/10.1371/journal.pone.0298424 [2] Mandal, N.; Surpeta, B.; Brezovsky, J. Reinforcing Tunnel Network Exploration in Proteins Using Gaussian Accelerated Molecular Dynamics. J. Chem. Inf. Model. 2024, 64(16), 6623-6635. https://doi.org/10.1021/acs.jcim.4c00966[3] Filipovic, J.; Vavra, O.; Plhak, J.; Bednar, D.; Marques, S. M.; Brezovsky, J.; Matyska, L.; Damborsky, J. CaverDock: A Novel Method for the Fast Analysis of Ligand Transport. IEEE/ACM Trans. Comput. Biol. Bioinform. 2020, 17(5), 1625–1638. https://doi.org/10.1109/TCBB.2019.2907492