# Presentation: 789266

## Molecular Biomedicine in the Era of 

**Molecular Biomedicine in the Era of **
**Teraflop Computing – Opportunities Ahead**

- Tamar Schlick

- Laxmikant Kale

- Steve Harvey

- Helmut Grubmueller

- John Board

- Andrew McCammon

- Ron Elber

- Robert Skeel

- Carol Post

- Bernard Brooks

- Charles Brooks

- Michelle Parrinello

- Peter Kollman

- Kim Baldridge

- Richard Friesner

- David Beveridge

- Jeffrey Skolnick

- Harel Weinstein

- Angel Garcia

- Dave Thirumalai

- Eric Jakobsson

- Zan Schulten

- Tom Ferrin

- Terry Stouch

*NIH Resource for Macromolecular Modeling and Bioinformatics*
*Theoretical Biophysics Group, Beckman Institute, UIUC*

## Steered Molecular Dynamics

**Why Steered Molecular Dynamics?**
- - Accelerates processes to simulation time scales (ns)
- Yields explanations of biopolymer mechanics
-  Finds underlying unbinding potentials

*NIH Resource for Macromolecular Modeling and Bioinformatics*
*Theoretical Biophysics Group, Beckman Institute, UIUC*

## Atomic Force Microscopy in vivo,in vitro,in silico

**Atomic Force Microscopy *****in vivo,******in vitro,******in silico***

**Prof. Klaus Schulten**

*NIH Resource for Macromolecular Modeling and Bioinformatics*
*Theoretical Biophysics Group, Beckman Institute, UIUC*

## Titin Ig Domain Extension

- SMD is performed on titin Ig domains using constant velocity and constant force protocols.

- Titin I27 topology

- AFM extension of titin Ig multimers, Reif *et al*., Science **276**, 1109 (1997)

*NIH Resource for Macromolecular Modeling and Bioinformatics*
*Theoretical Biophysics Group, Beckman Institute, UIUC*

## Interactive ModelingBinding path of retinal to bacterio-opsin (1)

-  Retinal deep in bacterio-opsin
-   binding cleft
-  How does it get in?
-  Use batch mode interactive steered
-   molecular dynamics to pull retinal out
-   of cleft, find possible binding path

-  10 path segments, 3 attempts each
-  Choose best attempt at 9 points during pull
-  Found path through membrane, and electrostatically attractive entrance window

*NIH Resource for Macromolecular Modeling and Bioinformatics*
*Theoretical Biophysics Group, Beckman Institute, UIUC*

## Interactive ModelingBinding path of retinal to bacterio-opsin (2)

- Interactive ModelingBinding path of retinal to bacterio-opsin (2)

- B. Isralewitz, S. Izrailev and K. Schulten, *Biophys. J.*, **73**, 2972-2979 (1997)

- Other systems studied: avidin-biotin: Izrailev *et al*., Biophys. J., **72**, 1568-1581 (1997); lipid-membrane: Stepaniants *et al*., J. Molec. Modeling, **3**, 473-475 (1997); retinoic acid receptor: Kosztin *et al*., Biophys. J., **76**, 188-197 (1999); actin phosphate release: Wriggers *et al*., Proteins, **35**, 262-273 (1999); titin: Lu *et al*., Biophys. J., **75**, 662-671 (1998); Lu and Schulten, Proteins, **35**, 453-463 (1999), Chem. Phys., **247**, 141-153 (1999); fibronectin: Krammer *et al*., PNAS, **96**, 1351-1356 (1999); bc1 complex: Izrailev *et al*, Biophys. J., **77**, 1753-1768 (1999)

*NIH Resource for Macromolecular Modeling and Bioinformatics*
*Theoretical Biophysics Group, Beckman Institute, UIUC*

## Quantitative Analysis of SMD

-  The potential of mean force (PMF) is reconstructed from time series of applied force and displacement
-  Non-equilibrium analysis based on the Langevin equation:
-     x = F(x,t) – dU/dx + (t)
-  Multiple trajectories can be combined to yield statistically significant results

*NIH Resource for Macromolecular Modeling and Bioinformatics*
*Theoretical Biophysics Group, Beckman Institute, UIUC*

## Reconstruction Methods Investigated

-  WHAM: generate probability data from the time series *x(t)* and reconstruct the potential assuming quasi-equilibrium
-  Gaussian Drift Method: measure the velocity *x(t)* and the size of the fluctuations
-  Least Square Method: the most probable PMF minimizes the Onsager-Machlup action, given *x(t)* and *F(t)*

- J. Gullingsrud, R. Braun and K. Schulten, J. Comp. Phys, **151**, 190-211 (1999)
- Earlier study: M. Balsera et al., Biophys. J., **73**, 1281-1287 (1997)

*NIH Resource for Macromolecular Modeling and Bioinformatics*
*Theoretical Biophysics Group, Beckman Institute, UIUC*

## Reconstructing Potentials from Time Series Data

- Which potential *U(x)*?

- Data from Langevin model

*NIH Resource for Macromolecular Modeling and Bioinformatics*
*Theoretical Biophysics Group, Beckman Institute, UIUC*

## Least Squares Method

*NIH Resource for Macromolecular Modeling and Bioinformatics*
*Theoretical Biophysics Group, Beckman Institute, UIUC*

## Reconstructing Potentials Using Full Onsager-Machlup Action and Multiple Trajectories

*NIH Resource for Macromolecular Modeling and Bioinformatics*
*Theoretical Biophysics Group, Beckman Institute, UIUC*

## Interactive Molecular Dynamics

- _Goals_
- Speed up slow events in molecular dynamics simulations.
- Assist in the discovery of new motions and pathways in biomolecules.
- Supply immediate feedback to researchers about the physical system.

*NIH Resource for Macromolecular Modeling and Bioinformatics*
*Theoretical Biophysics Group, Beckman Institute, UIUC*

- _Design_

**VMD**

**NAMD**

**BioCoRE**

- commands

- coordinates

## NAMD: Scalable Molecular Dynamics

- Parallel simulation of biomolecular systems
- Spatial decomposition for distributed memory
- Message driven for latency tolerance
- Object-oriented and implemented in C++

**Kalé *****et al.,***** J. Comp. Phys., 151, 283 (1999)**

- http://www.ks.uiuc.edu/Research/namd

*NIH Resource for Macromolecular Modeling and Bioinformatics*
*Theoretical Biophysics Group, Beckman Institute, UIUC*

## Interactive ModelingStructure based drug design

- Interactive ModelingStructure based drug design

*NIH Resource for Macromolecular Modeling and Bioinformatics*
*Theoretical Biophysics Group, Beckman Institute, UIUC*

- Interactive molecular dynamics will allow
- docking studies to incorporate
- the realistic motions of molecules

- Inhibitor SAD (selenazole-
- 4-carboxamide adenide dinucleotide

- Liver alcohol dehydrogenase

- For a system of this size (~15,000 atoms solvated), 0.5 ps/minute is possible on 64 nodes of Cray T3E.
- Factor of 50 increase in speed is desirable.

## VMD: Visual Molecular Dynamics 

**Key Features:**
- Display and animation of macromolecules
- Real-time interaction with molecular
- dynamics simulations
- Supports Windows 95/98/NT, and a wide
- variety of Unix platforms
- Hardware accelerated 3D rendering and
- stereoscopic display

- http://www.ks.uiuc.edu/Research/vmd/
**Humphrey *****et al.*****, J. Molec. Graphics, 14.1, 33 (1996)**

*NIH Resource for Macromolecular Modeling and Bioinformatics*
*Theoretical Biophysics Group, Beckman Institute, UIUC*

## How the connection works

-  The visualization program (VMD) and the simulation engine (NAMD) exchange commands and coordinates so that the user can interactively steer the simulation.
-  A collaboratory environment (BioCoRE) comlements IMD with the ability to start and monitor several jobs at once.

**VMD**

**NAMD**

**BioCoRE**

- commands

- coordinates

- find running jobs

- start NAMD

*NIH Resource for Macromolecular Modeling and Bioinformatics*
*Theoretical Biophysics Group, Beckman Institute, UIUC*

## A Haptic Device for IMD

-  **Grab Tool**: translate and rotate a molecule simultaneously
-  **Tug Tool**: steer a running simulation and receive interactive force feedback
-  **SMD Tool**: Apply a force along a chosen direction and record force vs. displacement

- A haptic device is the most natural tool with which to interact with a running simulation.
- The haptic device can function in a number of different modes in VMD, to fully utilize the device’s 6 DOF capability.

*NIH Resource for Macromolecular Modeling and Bioinformatics*
*Theoretical Biophysics Group, Beckman Institute, UIUC*

## Interactive Docking of Lactose lac Repressor

*Theoretical Biophysics Group, Beckman Institute, UIUC*

- Interactive Docking of Lactose *lac* Repressor

## Application to Gramicidin A System

- The SMD tool can be used to interactively steer the ion through the channel.
- The applied force vs. displacement is recorded for later use.

*NIH Resource for Macromolecular Modeling and Bioinformatics*
*Theoretical Biophysics Group, Beckman Institute, UIUC*

## Interactive Molecular Dynamics (IMD)

- Interactive Molecular dynamics (IMD) provides a direct network connection for efficient exchange of steering commands and simulation coordinates. It is a tool that can:
-  speed up slow events in molecular dynamics simulations
-  assist in the discovery of new motions and pathways in biomolecules
-  supply immediate feedback to researchers about the physical system
- IMD can easily be performed with the simulation engine running on remote supercomputers, e.g. NCSA, SDSC, PSC, etc, and the visualization done locally.

*NIH Resource for Macromolecular Modeling and Bioinformatics*
*Theoretical Biophysics Group, Beckman Institute, UIUC*

## Planned Work

- Support developing haptic technology, including torque response as well as
- relatively inexpensive force-feedback joysticks.
- Application to large macromolecular systems will take advantage of NAMD’s
- excellent scaling on multiprocessor and distributed machines.
- Quantitative analysis:
- 	1. Apply PMF analysis to force-displacement time series gathered during interactive sessions. (Gullingsrud et al., J. Comp. Phys., 151, 190-211, 1999)
- 	2. On the fly analysis of RMSD, correlation functions, etc.
- Development of visual computing environment for “hands-free” input.

*NIH Resource for Macromolecular Modeling and Bioinformatics*
*Theoretical Biophysics Group, Beckman Institute, UIUC*

## A visual computing environment for very large scale biomolecular modeling

*NIH Resource for Macromolecular Modeling and Bioinformatics*
*Theoretical Biophysics Group, Beckman Institute, UIUC*

## Gesture Recognition Setup

*NIH Resource for Macromolecular Modeling and Bioinformatics*
*Theoretical Biophysics Group, Beckman Institute, UIUC*

## Multimodal CESB

*NIH Resource for Macromolecular Modeling and Bioinformatics*
*Theoretical Biophysics Group, Beckman Institute, UIUC*

## Gesture Recognition in CESBRole of hand model gesture analysis

*NIH Resource for Macromolecular Modeling and Bioinformatics*
*Theoretical Biophysics Group, Beckman Institute, UIUC*

## Speech recognition setup

*NIH Resource for Macromolecular Modeling and Bioinformatics*
*Theoretical Biophysics Group, Beckman Institute, UIUC*

## Acknowledgements

*NIH Resource for Macromolecular Modeling and Bioinformatics*
*Theoretical Biophysics Group, Beckman Institute, UIUC*

- Theoretical Biophysics Group
- Beckman Institute, UIUC
- Ferenc Molnar
- Sergei Izrailev
- Hui Lu
- Rosemary Braun
- Dorina Kosztin
- Justin Gullingsrud
- Barry Isralewitz
- Michael Zeller
- Andrew Dalke
- Paul Greyson
- Jim Phillips
- John Stone
- William Humphrey

- Image Formation and Processing Group
- Beckman Institute, UIUC
- Thomas Huang
- Vladimir Pavlovic
- Yunxin Zhao
- Zion Lo
- Stephen Chu
- Prof. Rajeev Sharma
- The Pennsylvania State University