MDTAP: a tool to analyze permeation events across membrane proteins

Abstract

Motivation: Molecular dynamics (MD) simulations provide critical insights into the transport of solutes, solvents, and drug molecules across protein channels embedded in a membrane bilayer. However, identifying and analyzing the permeation events from complex simulation data remains as a challenging and laborious task. Thus, an automated tool that facilitates the capture of permeation events of any molecular type across any channel is essential to streamline MD trajectory analysis and enhance the understanding of biological processes in a timely manner.

Results: Molecular Dynamics Trajectory Analysis of Permeation (MDTAP) is a Linux/Mac-based software that automatically detects permeation events across membrane-embedded protein and nucleic acid channels. The tool accepts trajectories in DCD (CHARMM/NAMD) and PDB format (obtained from any MD simulation package) and employs bash scripts to analyze the input trajectories to characterize the molecular permeation. The efficiency of MDTAP is demonstrated using MD trajectories of Escherichia coli outer membrane protein Wzi and E. coli Aquaporin Z. MDTAP can also analyze permeation across heterogeneous lipid membranes and artificial nucleic acid channels, addressing their growing importance. Thus, MDTAP simplifies trajectory analysis and also reduces the need for manual inspection.

Availability and implementation: MDTAP is open-source and is freely available on GitHub (https://github.com/MBL-lab/MDTAP), including source code, installation instructions, and usage documentation.

Figure 1.

Methodological development of MDTAP. (A) A schematic representation describing complete and incomplete permeation events by considering the water-conducting E. coli Wzi protein channel (cartoon representation, PDB ID: 2YNK) as an example. Wzi in a periodic boundary condition is shown on the left. For the sake of clarity, POPE and POPG (3:1) membrane molecules are not shown. The water reservoir on either side of the channel is shown in line representation. While the light blue colored water molecule shows the complete permeation event, the dark blue colored water molecule shows an incomplete permeation. (B) Flowchart describing the methodology implemented in MDTAP to identify the permeation events in an automated fashion. See text for details. The yellow cylinder indicates the channel through which the molecule(s) is expected to permeate.

Figure 2.

Schematic representation describing the outputs generated by the nine different submodules of the “APM” (refer to Table 1 for the functionality details and Supplementary Fig. S2 for the interlink between these submodules) by considering E. coli Wzi trajectory (200 ns) (Sachdeva et al. 2016) as a case in point is shown. The channel’s position with respect to the Z-axis is obtained from the “Z-density profile” submodule and is used as the Z_max and Z_min values for the subsequent submodules. Similarly, the “XY area profile” submodule gives a clue about the channel’s position with respect to the XY plane. The list of atom numbers that are found to permeate across the channel is obtained from the “Permeation” submodule (viz., the atom numbers of those molecules that undergo complete or true permeation) and is used in the subsequent submodules (refer to Supplementary Fig. S2). The red-colored double hashtags (##) in the graph titles indicate that it is a representative output of the respective submodule.

Figure 3.

Graphical outputs generated by submodules 1, 2, 3, and 7 of APM: (A) A snapshot of the MD trajectory showing the bulk water (represented by spheres) translocation across the E. coli Wzi (cartoon representation) channel: (top) front view of the channel and (bottom) the concomitant “Number of water molecules in every 1 Å block versus Position along Z-coordinate (Å)” plot generated by the submodule “Z-density profile.” The dotted lines indicate the position of the channel in the Z-dimension. (B) (top) Top view of the Wzi channel and (bottom) the corresponding position of the channel in the XY plane projected onto the 1 Å block defined along the Z-axis (representative plot between 44–43 Å) generated by the “XY area profile” module. (C) The number of molecules within the channel (Z-coordinates between 40 and 60 Å as defined by Figure (A) (bottom)) is shown as a “Time (ps) versus Number of molecules” plot generated by the “Rate of change of molecules” submodule. A mean of ∼150 molecules is seen in the channel in accordance with the previous study (Sachdeva et al. 2016). (D) The path traced by the water molecule with atom number 37664 (oxygen) is shown as a “Time (ps) versus Z-coordinate (Å)” plot generated by the “Track molecule” submodule. This molecule takes about ∼50 ns (viz., enters and exits between ∼100 and 150 ns) to cross the channel from the periplasmic side to the extracellular side.