advances in protein modeling and protein-protein...

Advances in Protein Modeling and Advances in Protein Modeling and ProteinProtein--protein interactions in protein interactions in

Discovery StudioDiscovery Studio®®

This presentation and/or any related documents contains statements regarding our plans or expectations for future features, enhancements or functionalities of current or future products (collectively "Enhancements"). Our plans or expectations are subject to change at any time at our discretion. Accordingly, Accelrys is making no representation, undertaking no commitment or legal obligation to create, develop or license any product or Enhancements. The presentation, documents or any related statements are not intended to, nor shall, create any legal obligation upon Accelrys, and shall not be relied upon in purchasing any product. Any such obligation shall only result from a written agreement executed by both parties. In addition, information disclosed in this presentation and related documents, whether oral or written, is confidential or proprietary information of Accelrys. It shall be used only for the purpose of furthering our business relationship, and shall not be disclosed to third parties.

June 12, 2008

Francisco Hernandez-Guzman, Ph.D.Lead Solutions [email protected]

© 2008 Accelrys, Inc. 2

Agenda:

• What is Discovery Studio?• Advances in Protein Modeling

– General enhancements– Overall workflow for Homology Modeling– Specialty tools for Antibody Modeling

• Demo• Advances in modeling of protein-protein interactions

– Why in-silico modeling of protein-protein interactions?– Recent advances to our technology – Review of the science behind docking– Overall workflow used in protein-protein interactions

• Demo

• Q&A


What is Discovery Studio?

• Discovery Studio is a unified Life Science integrated environment to perform molecular modeling and simulations calculations such as:

– In silico Structure Based Drug Design– Rational Drug Design– Protein Modeling– Sequence Analysis– Molecular Dynamics Simulations– X-ray crystallography refinement

• Discovery Studio is tightly integrated to the SciTegic platform technology for superior technology development and customization

Discovery Studio Client

Discovery Studio Client ISV

Client

ISV Client

PP Web Client

PP Web Client PP Editor

Client

PP Editor Client

Statistics Chemistry Biology ISV CollectionMat SciReportingIntegration

Workflow PlatformWorkflow Platform

Scientific Workflow Solutions 3rdParty Applications

ScientificApplications

(Pipeline Pilot)

Discovery Studio®

Pipeline Pilot


Advances in Protein Modeling

• Major focus areas in DS Visualizer– Improved 3D graphical performance (Ribbons, sticks, etc)– Charts– Custom pharmacophore features– Sequence window (better sequence block management)

• Scripting– Several new APIs added– DS Command category fully supported– Many scripts available through the forum site (http://accelrys.org)

Other enhancements:

• Standardize atom order as part of cleaning procedure

• Added enhanced “Caps” to terminal residues

• Enhanced selection tools: intermolecular vs intramolecular

• The Align and Superimpose protocol has been enhanced to allow secondary structure information to be used in the alignment.

• Modifications have been made to the Align Structures and Align Structures (MODELER) protocols to automatically superimpose the structures after the alignment.

• The Refine Loops protocol has been enhanced to allow inclusion of ligands.


DEMO

• Specific enhancements– Graphical performance– Chart example using pK output– Sequence block management

• Homology Modeling Workflow– Template Search– Sequence Alignment– Structure Alignment– Homology Model Building– Loop refinement– (Antibody loop refinement)


Why Protein-protein interactions?

• Biological molecules in the body work together to elicit a response

• Need to have a physical understanding of macromolecular interactions– Provide a solid hypothesis for potential interactions

• Experimental methods– X-ray crystallography

• Difficult, slow, high degree of expertise• Experimental bias

• Applications:– Site directed mutagenesis, protein design, stability– X-ray crystallography– Molecular detection/screening– Affinity binding– Molecular aggregation


Advances in Protein-protein interactions

Protein-protein docking• ZDOCK Version upgraded

– New version ZDOCK 2.3 has a more detailed scoring function includingsolvation and electrostatic energy terms

• Added fast rescoring of docked poses with ZRANK to improve pose selection

• Streamlined interfaces for Protein-Protein Docking– Tool Panel in DS Client – Protocols



Protein-protein docking with: ZDOCK and ZRANKZDOCK: Rigid Body Docking

– Calculations based on Fast Fourier Transforms– Energy Terms:

• PSC – Pairwise Shape Complementarity (ZDock 2.1&2.3)» Favorable term measures number of receptor-ligand pairs within cutoff distance» Penalty for atomic overlap

• Electrostatics (ZDock 2.3)» Correlation between receptor potential and ligand charges

• Desolvation (ZDock 2.3)» ACE (Atomic Contact Energy)

R

L Y

Cor

rela

tion

X

IFT

FFT

FFT

Surface Interior Binding Site



Protein-protein docking with: ZDOCK and ZRANKZRANK: New Scoring Function

– Based on pairwise energy terms

dsds

lrreleclrreleclraeleclraelec

srrelecsrrelecsraelecsraelec

rvdWrvdWavdWavdW

EwEwEwEwEw

EwEw

ZR

+++++

++

=____

____

____ Van der Waals

electrostatics

Van der Waals

Brian Pierce and Zhiping Weng*, PROTEINS: Structure, Function, and Bioinformatics 67:1078–1086 (2007)


Refined Poses

RDOCK

no yes

ZDOCKPSC

Receptor Protein

LigandProtein

Binding Site Residues

TOP MZRANK

CLUSTER

Generate ligand

coordinate

DeltaG (ACE)

CHARMm 1st run no formal charges

CHARMm 2nd run with formal charges

Docked Poses

Protocols: Workflow Overview

ELEC&DS?

ZDOCKPSC+ELEC+DS

Top NZDOCK

ZRANK

ZDOCK Process Poses


Performance & Relative Timing

• Using additional ZDOCK terms (ZDock 2.3) improves performance over shape complementarity alone (ZDock 2.1)

• Using ZDock 2.3 roughly doubles – Computation Time– Memory Usageover ZDock 2.1

• ZRank calculation takes a fraction of the time of ZDock

• Used in combination with ZRank performance of ZDock2.3 and ZDock 2.1 are very similar


Added Benefits in Discovery Studio:

• Visualization/Tools (GUI)

• Clustering Methods

• Coarse grain parallelization

Workstation

Server Server Server Server


DEMO

• Protein-protein docking protocol setup

• ZRANK energy based scoring

• Analysis of results

• Visualization and Clustering


Conclusion

• Advances in Protein Modeling tools in Discovery Studio are designed to improve usability

• Inclusion of ligand information during loop refinement helps restrain loop conformations to improve protein-ligand interactions

• Addition of a new version of ZDOCK is designed to improve the prediction success rate of in silico protein-protein interaction studies

• Integration of ZDOCK, ZRANK and RDOCK to Discovery Studio allows for easier preparation and analysis of the data, as well as deployment of calculations in parallel

• Graphical utilities complement workflow by providing interactive analysis and manipulation tools for uncovering plausible protein-protein complexes


Acknowledgements

• Marc Faschnat

• Tina Yeh

• Lisa Yan

• Paul Flook

• Shikha O’Brien

• Z-Lab (Prof. Zhiping Weng – Boston University)


Thank you!!!

• Thank You for attending today’s webinar. If you have any further questions please e-mail me at: [email protected]

• You can also contact us using the form on our website: http://accelrys.com/company/contact/

• We will be exhibiting at the following upcoming events:– CHI Protein Kinase Targets (June 23 – 25, Boston, Booth #4)– CHI Structure Based Design (June 25 – 27, Boston, Booth #7)– Drug Discovery Technology and Development (August 4 – 7, Boston, Booth #512)– ACS Fall 2008 (August 17 – 21, Philadelphia, Booth #211)

• Reminder: the next webinar in this series will be:Physics Based Protein Ionization and pK Estimation

June 19, 2008 at 7am PST and 10am PST


References:

• Chen, R., Li, L. & Weng, Z. (2003) ZDOCK: An Initial-stage Protein Docking Algorithm. Proteins. 52(1):80-7

• Li, L., Chen, R. & Weng, Z. (2003) RDOCK: Refinement of Rigid-body Protein Docking Predictions. Proteins. 53:693-707.

• Qasim MA, et al. (2006) Despite Having a Common P1 Leu, Eglin C Inhibits α-Lytic Proteinase a Million-fold More Strongly than Does Turkey Ovomucoid Third Domain. Biochemistry. 45(38), 11342-11348

• Wiehe K, Pierce B, Mintseris J, Tong W, Anderson R, Chen R, Weng Z (2005) ZDOCK and RDOCK performance in CAPRI rounds 3, 4, and 5. Proteins.60(2):207-213


Additional Selected References:

• Brooks,B.R.,Bruccoleri,R.E.,Olafson,B.D.,States,D.J.,Swaminathan,S.,and Karplus, M., “CHARMM: A program for macromolecular energy, minimization, and dynamics calculations,” J. Comput. Chem. , 1983 , 4 , 187-217

• Chen R, Li L, Weng Z, ZDOCK: An Initial-stage Protein-Docking Algorithm. Proteins, 2003 , 52 , 80 – 87

• Eswar, N., Eramian, D., Webb, B., Shen, M., Sali. A. Protein Structure Modeling With MODELLER. Current Protocols in Bioinformatics John Wiley & Sons, Inc. , 2006, Supplement 15 , 5.6.1-5.6.30

• Spassov, V., Yan, L. and Flook, P. “The Dominant Role of Side-chain Backbone Interactions in Structural Realization of Amino-acid Code. ChiRotor: a Side-chain Prediction Algorithm Based on Side-chain Backbone Interactions,” Protein Science , 2007

• Spassov, VZ, et al. “LOOPER: A Molecular Mechanics Based Algorithm for Protein Loop Prediction”, Accepted, Protein Engineering, Design and Selection

• Warren, GL et al. “A critical assessment of docking programs and scoring functions”, J. Med. Chem . 2006 , 49(20) , 5912-31

advances in protein modeling and protein-protein...

Documents