T-Analyst: a program for efficient analysis of protein conformational changes by torsion angles

Abstract

T-Analyst is a user-friendly computer program for analyzing trajectories from molecular modeling. Instead of using Cartesian coordinates for protein conformational analysis, T-Analyst is based on internal bond-angle-torsion coordinates in which internal torsion angle movements, such as side-chain rotations, can be easily detected. The program computes entropy and automatically detects and corrects angle periodicity to produce accurate rotameric states of dihedrals. It also clusters multiple conformations and detects dihedral rotations that contribute hinge-like motions. Correlated motions between selected dihedrals can also be observed from the correlation map. T-Analyst focuses on showing changes in protein flexibility between different states and selecting representative protein conformations for molecular docking studies. The program is provided with instructions and full source code in Perl.

Fig. 1

Torsion angle distribution of side-chain χ² of Ile153 of TRPS. Torsion angle: a before angle correction and b after angle correction. Histogram of torsion angle distribution output by T-Analyst: c before angle correction and d after angle correction

Fig. 2

Analysis of the hinge regions of HIV-1 protease. a An open conformation of HIV-1 protease obtained from the MD simulation. Flaps: residues 43–58, yellow; elbows: residues 37–42; hinge: Gly 40, red. b RMSF of Cα atoms. c Distance between two flap tips: residues Ile 50 and Ile 50′. d Ψ angle distribution of Gly 40′; values within the dashed lines, between 720 and 880 ps, correspond to open flap conformations shown in c

Fig. 3

Clustering conformations of TRPS. a–d Ligand-free state, e–h ligand-bound state. Torsion angle distribution of side-chain χ³ of Glu 49 in a ligand-free and e ligand-bound state. Torsion angle distribution of side-chain χ² of Ile 153 in b ligand-free and f ligand-bound state. c, g RMSD of Glu 49 and Ile 153 after structure alignment. d, h conformational groups computed by T-Analyst over the course of MD simulations. Each small diamond represents one frame

Fig. 4

Snapshots of surrounding residues of Glu 49 in a ligand-bound and b ligand-free state. Grey dotted lines indicate stable hydrogen-bonds in a and green dotted lines indicate weak hydrogen-bonds in b. Red dashed lines indicate the distance between Tyr173:OH and Glu49:CD. The circle labeled with IGP in b indicates the position of the ligand binding pocket

Fig. 5

Entropy distributions in the binding site of TRPS. a Entropy distribution of Ψ torsion angles of residues within 8Å of ligand IGP and b side-chain torsion angles that directly interact with IGP

Fig. 6

Structure anatomy of HIV-1 protease and correlation maps of one subunit of HIV-1 protease in BAT coordinates and Cartesian coordinates. a Structure anatomy of HIV-1 protease. Color indicates distinct regions. Flaps: residues 43–58, red; flap tips: residues 49–52, yellow; flap elbows: residues 37–42, magenta; cantilevers: residues 59–75, green; fulcrums: residues 10–23, orange; loop area near flaps: residues 76–84, grey; and interleaved β-strand motif forming the dimer interface: residues 1–4 and 96–99, blue/cyan. b Φ and Ψ torsion angle correlation map generated by T-Analyst using BAT coordinates. Yellow lines and boxes indicate correlations between I: fulcrum; II: flap elbow, III: flap with flap elbow, IV: flap, V: flap tip, VI: flap elbow with cantilevel, VII: flap with cantilevel, VIII: cantilevel, IX: fulcrum with loop, and X: loop. c Correlation map generated by the use of the backbone Cα and N atoms in the Cartesian coordinates with the Bio3D package