Protein-Ligand Analysis with SID

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1 Protein-Ligand Analysis with SID A new post-simulation analysis tool Dmitry Lupyan, PhD

2 Understanding molecular processes with MD Drug discovery and design Protein-protein interactions + Protein-DNA interactions Protein folding Liang Z et al., PLOSOne 2011 van Dijk et al., Nucl. Acid Res Stranges et al., 2011 PNAS

Syk interactions w/inhibitor Spleen Tyrosine Kinase (Syk) with type-ii inhibitor (3tub) Syk interactions with the ligand described as: "The quinoline occupies the ATP pocket interacting with Ala451.

3 Syk interactions w/inhibitor Spleen Tyrosine Kinase (Syk) with type-ii inhibitor (3tub) Syk interactions with the ligand described as: "The quinoline occupies the ATP pocket interacting with Ala451. The urea makes an H-bond to Asp512 of the DFG sequence as well as Glu420 off the Chelix. The cyclopropyl aryl induces a DFG-out conformation with terminal aryl ring occupying the DFG-out pocket." Lovering et. al. Chem Biol Drug Des (80) 2012

4 Syk interactions w/inhibitor publication Schrödinger tools PDB

5 Typical workflow for analyzing MD simulation of a Protein-Ligand Complex Run MD simulation Check system energy, box size, temperature Calculate RMSD of the protein Calculate RMSD of the ligand Calculate RMSF of the protein Scale RMSF and check if B factor agree with RMSF Figure out if high RMSF values correlate to loops 6. Display protein within 3 Å of a ligand Play/animate trajectory several times Setup up to 100 various measurements to figure out what are the predominant protein-ligand interactions 7. Generate snapshots and plots to communicate my findings 8. Put together a PowerPoint or write up a report

6 Analyzing MD simulation of a Protein-Ligand Complex with SID 1. Run MD simulation 2. Run analysis manually: launch SID automatically: by adding pl_analysis{ } to the msj file 3. View results in SID panel, or export as PDF report/images

$Run analysis manually: launch SID automatically: by adding pl_analysis{} to the msj file 3.$

7 Analyzing MD simulation of a Protein-Ligand Complex with SID 1. Run MD simulation 2. Run analysis manually: launch SID automatically: by adding pl_analysis{} to the msj file 3. View results in SID panel, or export as PDF report/images Contacts Contacts RMSD RMSF RMSF Rot. Bonds

8 Computed Properties Protein RMSD/RMSF Ligand RMSD/RMSF Secondary structure elements Protein-Ligand contacts Ligand conformational analysis Applications Desmond Simulation Interactions Diagram

9 Protein-Ligand RMSD (PL-RMSD Tab) Protein RMSD Ligand RMSD C-alpha Backbone Side chains Heavy atoms Aligned on Ligand Aligned on Protein Plot feedback

10 Protein RMSF (P-RMSF Tab) Protein RMSF Additionally C-alpha Backbone Side chains Heavy atoms Secondary Structure B factor Ligand contacts Plot feedback

11 Ligand RMSF (L-RMSF Tab) Ligand RMSF Aligned on protein Aligned on ligand Interactive 2d feedback plot feedback

12 Protein-Ligand Contacts (PL-Contacts Tab) Histogram 4 main contact types 11 contact subtypes toggle on/off contacts Timeline View H-bonds Hydrophobic Ionic Water bridges Total # of contacts When/where and how many contact occurred Navigate the trajectory

13 Protein-Ligand Contacts (PL-Contacts Tab) Histogram 4 main contact types H-bonds Hydrophobic Ionic Water bridges

14 Protein-Ligand Contacts (PL-Contacts Tab) Histogram 4 main contact types H-bonds Hydrophobic Ionic Water bridges

15 Protein-Ligand Contacts (PL-Contacts Tab) Timeline View Total # of contacts When/where and how many contact occurred

16 Ligand-Protein Contacts (LP-Contacts Tab) Contacts mapped onto 2-D ligand Change interaction cutoff Navigate the trajectory

17 Ligand Torsions/Rotatable Bonds (L-Torsions Tab) Timeseries of all RB in the ligand Distribution of RB Show torsion potential (OPLS_2005) of all RB

18 Ligand Torsions/Rotatable Bonds (L-Torsions Tab) Timeseries of all RB in the ligand Distribution of RB Show torsion potential (OPLS_2005) of all RB

19 Pyridine Ring Flip N

20 Pyridine Ring Flip publication (3tub.pdb)

21 Does MD add anything new? Syk interactions in publication: "The quinoline occupies the ATP pocket interacting with Ala451. The urea makes an Hbond to Asp512 of the DFG sequence as well as Glu420 off the C-helix. The cyclopropyl aryl induces a DFG-out conformation with terminal aryl ring occupying the DFG-out pocket." With MD analysis, description now can be rewritten: "The quinoline occupies the solvent accessible ATP pocket and H-bonds with the backbone Ala451 via transient interactions. The urea is coordinated predominantly by Glu420 and Asp512, via side chain and backbone, respectively. The pyridine interacts with Phe513 via a intermittent Pi-Pi stacking interaction, as well as Lys402 via side chain H-bond. The cyclopropyl aryl induces a DFG-out conformation with terminal aryl ring, from Phe490, occupying the DFG-out pocket."

22 Export Data, images, create PDF Reports Easily export all plots in PNG and SVG formats Easily export all data into a text file (fixed width) Export PDF report with detail description for each plot to your collegue for ELN for future reference for printing it out and taking it home

23 New direction... Intuitive and easy to use Automation Standardize set of analyses for a given task Used for validation as well as exploration Emphasize visualization is the protein stable? does the ligand remain bound? what type of H-bond or Hydrophobic interaction is this? publication/presentation ready Results should be easy to share Modular framework for customization

24 What's next for prot-lig interactions? SSE GUI panel more interaction types: Ion and metal interactions halogen pi-amide symmetry for ligand RMSD ligand properties: intramolecular hydrogen bonds ionic hydrophobic radius of gyration Mol-SA/SASA/PSA Energetic analyses Workspace interactivity SiteMap integration Fingerprints Clustering Compare simulations Better characterization of ligandwater interactions

25 Thank You! PyDev Pat Lorton, PyD Alex Smondyrev, PhD Kevin Keating, PhD Nicola Zonta, PhD Desmond Teng Lin, PhD Byungchan Kim, PhD Yujie Wu, PhD AppSci/Science Woody Sherman, PhD Thijs Beuming, PhD Dora Warshaviak, PhD Robert Abel, PhD Goran Krilov, PhD UI/UX Mihai Coman Evan Sheehan, MA Evelyn Chambers

26 More information on SID Video tutorial: Desmond User Manual In Maestro, Help > Manuals Index > Desmond User Manual Newsletter: LinkedIn: Dmitry Lupyan

Protocol S1: Supporting Information

Protocol S1: Supporting Information Basis for the specificity of the kinase domain of Abl for peptide substrates The crystal structures reported in this work were obtained using two different ATP analog-peptide