V o l . l l No:5 J . o f C o m p u t . Sci. & T e c h n o l . S e p t e m b e r 1996

Applying Virtual Reality to Molecular Graphics System

C h a n g N o Yoon* , M y u n g H w a n Chi* , H e e d o n g K o t a n d J o n g s e i P a r k *

* Doping Control Center, ~ CAD~CAM Lab Korea Institute of Science and Technology

P.O. Box 131, Cheongryang, Seoul 130-650, Korea E-mail: cody@kistmail.kist.re.kr

Received July 17, 1995; revised May 27, 1996.

A b s t r a c t

Molecular graphics can be thought of as a window to the computer through which the chemist expresses ideas for computat ional evaluation and receives results in an understandable form. Furthermore, with beautiful graphic images it can give out the realistic molecular model like a real thing in real world. Molecule has various properties including volume, electronic, van der Waals forces, etc. These properties are very important to understand the molecular world. So if the virtual reality tools are used, then the imaginary world can be studied intuitively by touching and feeling a tremendous amount of data. Computat ional chemistry generates such amount of molecular proper ty da ta through supercomputing with molecular simulation experiment. One of the objects to investigate the molecular world is to understand the intermolecutar interaction such as drug-receptor interaction. Another thing is to measure the geometrical da ta in moIecular architecture. Virtual reality system provides the easiest way to meet these objects. This kind of simple system changes a numerical data set, which is very difficult to deal with, into a visible and understandable data set. Recently two functions of such a system were improved to get an insight into biomolecular interaction. The first one is a real t ime force generation during navigation in macromoIecular environment. An cylindrical arrow shows the magnitude and direction of molecular force. The second one is to see a molecular vibration such as a concerted motion of the binding site in protein molecule. So one can understand the molecular shape change for drug- receptor docking procedure. But some problems which are difficult to solve still remain.

K e y w o r d s : Molecular graphics, molecular docking, virtuM reality, force vector, real-time docking.

1 I n t r o d u c t i o n

M o l e c u l a r g raph ics s y s t e m is now recognized as an essent ia l tool in t he life a n d

m a t e r i a l sciences where the s t r u c t u r a l s tudies a t molecu la r level are ve ry i m p o r t a n t [1-4].

This work was supported by the Korea Institute of Science and Technology under grant numbers 2E13410 and V00105. This paper was reported at the International Workshop on Virtual Reality and Scientific Visualization in Hangzhou, China, in April 1995.

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Recent advances in molecular biology and genetic engineering have ted to the in- creased commercial interest in the potential to design proteins with enhanced or new properties and to produce improved drugs, hormones, industrial enzymes, agro- chemicals, biocatalysts and food proteins. These progresses are accelerated by the molecular structural information. Thus we have to investigate the three-dimensional molecular structures, calculate the intermolecular forces and rationalize the struc- tural changes to get more understanding of the physicochemical properties in such molecular level studies. But it is not easy to control the molecular structural op- eration in the computer screen and is difficult to estimate the molecular shape and size, especially in the molecular docking experiment.

Recently virtual reality technique is used down to the size of molecule [5-61. But we need to use more intuitive user interface of virtual reality system to understand the structures of macromolecules and how the structures related to their function. This work is a part of our ongoing project in virtual reality application, in which we incorporate the simple virtual reality technique such as stereoview and spaceball into the molecular graphics system.

2 Molecular Graphics Sys tem

2.1 H a r d w a r e System

SpacebaiI [SpacebalI Technologies Inc.] input device controls the intuitive smooth operation of the molecular structure which includes translation and rotation during the molecular navigation and docking. CrystalEye [Stereographics Inc.] gives us a stereoview of the interior and exterior shapes of the target macromolecules. Crimson workstation with one Reality Engine of SGI [Silicon Graphics Inc.[ is used as the main system, see Fig.1.

2.2 S o f t w a r e System

Our molecular graphics system can build the molecular structure, operate the structure to rotate and translate to any reference axis, and change its conformation with some rotation to the internal torsion angle of the molecule. In order to study the molecular interaction, it can monitor the structural and energetical change with the molecular docking procedure. Using various kinds of graphical representation helps us to understand the molecular properties such as molecular size, electrostatic field, and backbone skeleton. GL graphics library of Silicon Graphics, Inc. is also used.

2.2.1 M o l e c u l a r M o d e l l i n g

In order to generate a molecular structure the Cartesian coordinates of the target molecule are taken from the Brookhaven Protein Data BankF1. These structural data are compiled into one graphical object, which is constructed by compiling and

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drawing each graphical object in hierarchical manner . So it is convenient to traverse the object tree and to manipulate any particular object.

2.2.2 Stereo V i e w Di sp lay

The z- and double-buffer modes are used to draw the graphical object for fast hidden line removal and smooth structural manipulation. And the left and right eye views are displayed on the top and bot tom half of the screen respectively. Then the stereo view displaying is accomplished by using the CrystalEye device. The device makes it possible to see both images, the left and right views , in stereo.

Fig.1. Molecular graphics system. Fig.2. Force vector generation during docking procedure.

3 Virtual Reality Implementat ion

Some characteristics of our system involve the interactive visualization of struc- ture and properties of molecules with three-dimensional view and the intuitive ma- nipulation of molecular structures by the user with the six degrees of freedom op- eration. And molecular force vectors are generated by the real-time calculation for the interface with the force-feedback device.

3 .1 R e a l - T i m e F o r c e V e c t o r G e n e r a t i o n

Molecular docking between the host and guest molecules is resulted from the intermolecular forces exerted from each other. Intermotecular force calculation needs a large amount of computat ion with potential energy functions and their derivatives.

Molecular systems in biological studies have a large number of atoms, which is usually more than ten thousands. Each a tom interacts with others in several kinds of energetical ways including van der Waals and electrostatic energies. Although only the pairwise interaction between them is considered, a t remendous amount of comput ing time is needed. So we simplify the force vector calculation for the real-time docking.

We assumed that the target molecular system is not structurally changed so the molecular field around the system is constant during docking procedure. Therefore if we have the value of the initial molecular field at an arbi trary position surrounding

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the target system, then the computing time to obtain the force vector at the position can be reduced. To calculate the initial field the three-dimensional grid points are determined around the target system. At each grid position molecular interaction energy Eij and molecular force Fi due to the host-guest molecular interaction are calculated as follows,

A{j Bij + ei " e.__._i i (1) 6 E i j - rl f rij rij

where Aii and Bij are obtained from the atomic parameters Ai, Aj, Bi and Bj; ei and ej are the net atomic charges of atoms i and j; and rij is the distance betweeh atoms i and j.

~'~N ( dEij ~ Fi (2)

.1 where j ' s are N atoms which comprise the target molecular system,

Therefore, we now have the initial values at each grid point. So the navigation molecule will be affected by the molecular force which can be calculated as a sum of the atomic force vectors (Fig.2). This procedure dramatically reduces the computing time for molecular-force generation.

4 Example of the Model Sys tem

This interactive molecular graphics system has been applied to navigate protein molecules, called Major Histocompatibility Complex (MHC) molecule. The molecule is very important in human immune system, which has a binding groove to interact with the antigenic peptide molecule. This peptide molecule will navigate the MHC molecular system. So structural data files of the MHC molecule and the modal peptide molecule are loaded. Then the docking procedure will start with this model system.

First of all the view point is set to the center of the model peptide molecule. Then spacebM1 is attached to the peptide. We can operate easily the rotation and translation of the molecule with six degrees of freedom. When going into the MHC molecular system (Figs.3 and 4), the net force vector is displayed on the screen with the cylindrical arrow (Fig.2). And also the van der Waals overlaps between the atoms of peptide and MHC molecules are avoided. At any point where we want to see the molecular motion, the molecular graphics system is able to show the molecular movement using the historical trajectory file resulted from the molecular simulation. So we can investigate the binding pocket fluctuation and determine whether the navigating peptide molecule will fit the pocket or not.

5 Conc lus ion

Molecular graphics system interfaced with VR technique has some advantages, one of which is a smooth operation of molecular structure with six degrees of freedom. Another advantage is a force feedback to give us information about the molecular

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force. Thus the sys t em wi th 3D s te reoview gives us an immers ive effect dur ing the

molecular docking p rocedure .

Fig.3. Molecular navigation in MHC molecular system.

r . % - . . . . . . .

Fig.4. Molecular navigation near the binding pocket in MHC molecular system.

R e f e r e n c e s

[1] Fujita T. Using CAD to design receptor targeting of potent drugs. Computer-Aided Design, 1987, 19: 91-94.

[2] Fujii I, Morimoto Y, Higuchi Y, Yasuoka N. XELE--A polypeptide model-building program for a graphics workstation. Journal of Molecular Graphics, 1992, 10: 185-189.

[3] Badel A, Mornon J P, Hazout S. Searching for geometric molecular shape complementarity using bidimensional surface profiles. Journal of Molecular Graphics, 1992, 10: 205-211.

[4] Goodsell D S, Olson A J. Molecular illustration in black and white. Journal of Molecular Graphics, 1992, 10: 235-237.

[5] Bergman L D, Richardson J S, Richardson D C, Brooks F P, Jr. VIEW--An exploratory molecular visualization system with user-definable interaction sequences. In Computer Graph- ics Proceedings, Annual Conference Series, pp. 117-126, 1993.

[6] Brooks F P, Jr., Ouh-Young M, Batter J J, Kilpatrick P J. Project GROPE-haptic displays for scientific visualization. Computer Graphics, 1990, 24: 177-185.

[7] Bernstein F C, Koetzle T F, Williams G J B, Jr., Meyer D F, Brice M D, Rodgers J R, Kennard O, Shimanouchi T, Tasumi M. The protein data bank: A computer-based archival file for macromolecular structures. Journal of Molecular Biology, 1977, 112: 535-542.

C h a n g N o Y O O N is currently a principal research scientist at the Doping Control Center, Korea Institute of Science and Technology (KIST). He received his B.S. degree in Chemistry from Yonsei University in 1980. Then he received his M.S. degree in Physical Chemistry and his Ph.D. degree in Computational Chemistry both from Korea Advanced Institute of Science and Technology. He joined the KIST in 1985, and has been doing research work on Drug Analysis and Data Management for Seoul Olympic Games, Molecular Modelling and Graphics, Scientific Visualization, and Molecular Simulation.

M y u n g I4wan C H I is currently a researcher at the Doping Control Center, Korea Institute of Science and Technology. He received his B.S. degree in applied physics from Inha University in 1985. Since joining KIST in 1985, he has been doing research on data processing for Seoul Olympic Games, Scientific visualization, and Molecular modelling.