interactive animation in molecular dynamics

2
We discuss here the use of still frames showing the trajectory of certain atoms. These still frames have several advantages: l Some features are more easily seen than with animation. * A complete time slice may be seen at a single glance. l Cheaper hardware may be used. l Results are more easily published. The user operates in the following steps: l Run the simulation. l Load the result of the simulation into a database. 0 Prepare the picture. l Interact with the picture. Simulation and data loading is covered in a paper on animation (see Abstract 21). The picture is prepared as a set of 4D graphics primitives where the fourth dimension is time (frame number). The usual way to do this is to select a portion of the molecule and a set of frames. The last frame is shown with a stick and ball representation which may be full bond, mainchain or virtual bond. The path of each atom is then shown in a contrasting colour if hardware permits. The picture may be controlled in various ways. Conventional rotate, pan and zoom controls change the viewing transform, using conventional 3D to 2D mapping. The mapping of time onto the 2D display surface is also controlled. Thus we have a 4D to 2D mapping. Here is a scenario of how we use the picture control when viewing the results of molecular dynamics simulations. We colour the stick picture green, and the trajectory red. We first rotate the picture to maximize the red around the area of interest. This gives us a view showing most equivalent representations to emphasize the movement of surfaces. Displays are prepared by the user within the database. Atable withcolumns(xl,yl,zl, rl,x2, y2,z2,t2)is then converted into 4D lines, and a table with columns (x, y, z, t) into balls or other markers. A line (Xl (0, yl (t), zl (4. 6 x2 (4, y2 (0, 22 (4, 0 is drawn between bonded atoms 1 and 2 for the main molecule picture. A line (x(&i), y (t-i), z (t-i), t, x (t-i-I), y (t-i-l), z (t-i-1)) is drawn to show the trajectory of an atom, where x (t) represents the x coordinate of an atom at time t, and so on, and i is a frame index. These tables are generated for a particular picture using the join, project and the other relational operators. The display mainly used for this work was the IBM 3279, operated from our software via the IBM GDDM package, and all running on an IBM 3031. This cannot perform transformation in real time, but is easy to programme and provides colour. We have also experimented with a Vector Genera1 3300. This does permit realtime view transformation. However, these are provided by special 3D transformations hardware; it has not been designed to permit 4D transformations. Programming for 4D has been tricky, and so far we have only succeeded with display lists of about 50 4D lines. Volume 1 Number 2 June 1983 We will probably experiment with real time 3D rotation, combined with slower interaction with the time mapping. 21 ‘Interactive animation in molecular dynamics’ Todd, S and Haneef, I IBM UK Scientific Centre, Athelstan House, St Clement St, Winchester, Hampshire, UK Molecular dynamics simulations produce very large output. The output is usually in a form that is rather difficult to understand. We have built a system to permit the output of such simulations to be viewed as an interactive animated sequence. The user prepares for the animation with the following steps: * Run the simulation. e Load the result of the simulation into a database. 0 Prepare a set of picture frames, one per time step. l Run the interactive animation. The simulation is run outside our system. For the experiments so far, we have taken data on APP (Avian Pancreatic PoIypeptide) from a simulation run by W van Gunsteren and I Haneef. The total simulation ran on a set of four molecules in water solvent, and was run for 12 ps in 240 steps. The database used in our system is the Peterlee Relational Test Vehicle (see Abstract 13). Simulation output data is converted to a fixed file form, with data in orthogonal coordinates. To reduce the amount of data in our first experiments, we extracted only 30 frames, every third frame from the first 90 frames. Further, we did not load the hydrogen atoms and water molecules. The fixed files are loaded into the database by a standard database utility. The data is prepared for display using the facilities of the system. These include the ability to select portions of the molecule, to highlight or label particular features and to generate bond, mainchain or backbone representations. We intend to add surface representation soon. The preparation of each frame for an animation is exactly the same as for fixed pictures, so any feature added for fixed pictures is available for animation. For example, we are able to animate distance matrices (see Abstract 12). We hope to prepare special code for the production of a sequence of frames that takes advantage of the similarity of frames. This will reduce the current frame generation time of around 30 s/frame by at least a factor of 10. Prepared frames are saved on disc. The animation is run specifying a first and last frame number. When the sequence is complete, animation may be stopped, or the sequence automatically rerun, of rerun in reverse. The user has interactive control over the running animation in several ways. He controls the angle of view of the animation by a tiller (3D joystick). He controls the scale and panning from a tablet. (Not operational at 14 January 1983.) He controls the speed and direction from the terminal function keys, in one of two ways. o He may change the step used in the loop controlling frame display. This controls direction 55

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Page 1: Interactive animation in molecular dynamics

We discuss here the use of still frames showing the trajectory of certain atoms. These still frames have several advantages:

l Some features are more easily seen than with animation.

* A complete time slice may be seen at a single glance. l Cheaper hardware may be used. l Results are more easily published.

The user operates in the following steps:

l Run the simulation. l Load the result of the simulation into a database. 0 Prepare the picture. l Interact with the picture.

Simulation and data loading is covered in a paper on animation (see Abstract 21).

The picture is prepared as a set of 4D graphics primitives where the fourth dimension is time (frame number). The usual way to do this is to select a portion of the molecule and a set of frames. The last frame is shown with a stick and ball representation which may be full bond, mainchain or virtual bond. The path of each atom is then shown in a contrasting colour if hardware permits.

The picture may be controlled in various ways. Conventional rotate, pan and zoom controls change the viewing transform, using conventional 3D to 2D mapping. The mapping of time onto the 2D display surface is also controlled. Thus we have a 4D to 2D mapping.

Here is a scenario of how we use the picture control when viewing the results of molecular dynamics simulations. We colour the stick picture green, and the trajectory red. We first rotate the picture to maximize the red around the area of interest. This gives us a view showing most equivalent representations to emphasize the movement of surfaces.

Displays are prepared by the user within the database. Atable withcolumns(xl,yl,zl, rl,x2, y2,z2,t2)is then converted into 4D lines, and a table with columns (x, y, z, t) into balls or other markers. A line

(Xl (0, yl (t), zl (4. 6 x2 (4, y2 (0, 22 (4, 0

is drawn between bonded atoms 1 and 2 for the main molecule picture. A line

(x(&i), y (t-i), z (t-i), t, x (t-i-I), y (t-i-l), z (t-i-1))

is drawn to show the trajectory of an atom, where x (t) represents the x coordinate of an atom at time t, and so on, and i is a frame index. These tables are generated for a particular picture using the join, project and the other relational operators.

The display mainly used for this work was the IBM 3279, operated from our software via the IBM GDDM package, and all running on an IBM 3031. This cannot perform transformation in real time, but is easy to programme and provides colour. We have also experimented with a Vector Genera1 3300. This does permit realtime view transformation. However, these are provided by special 3D transformations hardware; it has not been designed to permit 4D transformations. Programming for 4D has been tricky, and so far we have only succeeded with display lists of about 50 4D lines.

Volume 1 Number 2 June 1983

We will probably experiment with real time 3D rotation, combined with slower interaction with the time mapping.

21 ‘Interactive animation in molecular dynamics’ Todd, S and Haneef, I IBM UK Scientific Centre, Athelstan House, St Clement St, Winchester, Hampshire, UK

Molecular dynamics simulations produce very large output. The output is usually in a form that is rather difficult to understand. We have built a system to permit the output of such simulations to be viewed as an interactive animated sequence. The user prepares for the animation with the following steps:

* Run the simulation. e Load the result of the simulation into a database. 0 Prepare a set of picture frames, one per time step. l Run the interactive animation.

The simulation is run outside our system. For the experiments so far, we have taken data on APP (Avian Pancreatic PoIypeptide) from a simulation run by W van Gunsteren and I Haneef.

The total simulation ran on a set of four molecules in water solvent, and was run for 12 ps in 240 steps.

The database used in our system is the Peterlee Relational Test Vehicle (see Abstract 13). Simulation output data is converted to a fixed file form, with data in orthogonal coordinates. To reduce the amount of data in our first experiments, we extracted only 30 frames, every third frame from the first 90 frames. Further, we did not load the hydrogen atoms and water molecules. The fixed files are loaded into the database by a standard database utility.

The data is prepared for display using the facilities of the system. These include the ability to select portions of the molecule, to highlight or label particular features and to generate bond, mainchain or backbone representations. We intend to add surface representation soon.

The preparation of each frame for an animation is exactly the same as for fixed pictures, so any feature added for fixed pictures is available for animation. For example, we are able to animate distance matrices (see Abstract 12). We hope to prepare special code for the production of a sequence of frames that takes advantage of the similarity of frames. This will reduce the current frame generation time of around 30 s/frame by at least a factor of 10. Prepared frames are saved on disc.

The animation is run specifying a first and last frame number. When the sequence is complete, animation may be stopped, or the sequence automatically rerun, of rerun in reverse. The user has interactive control over the running animation in several ways.

He controls the angle of view of the animation by a tiller (3D joystick). He controls the scale and panning from a tablet. (Not operational at 14 January 1983.) He controls the speed and direction from the terminal function keys, in one of two ways. o He may change the step used in the loop

controlling frame display. This controls direction

55

Page 2: Interactive animation in molecular dynamics

and gross speed. o He may change the number of refresh cycles for

each frame before the next frame is shown. This controls speed.

We intend to implement control of the sequence from the tablet by using the tablet position either directly to control frame number, or to control speed and direction.

The hardware consists of an IBM 3031 mainframe, an IBM Series/l mini, and a Vector General 3300. A key part of the design is a channel connection between the computers (about 1 Mbyte/s), and a DMA connection to the Vector General (over 1 Mbyte/s).

All preparation is done on the mainframe, and the frames to be used in an animation are stored in the virtual storage of the mainframe. (We use a virtual storage of about 4 Mbyte, the machine has 8 real Mbytes.) The mainfr~e sends frames via the Series/l to the Vector General. The frames are chosen by a program which monitors the function keys, and the rate is controlled by interrupts from the Series/l. The Series/ 1 monitors the tiller and tablet to control the rotation, pan and zoom registers of the Vector General. It also monitors the refresh cycle to send an interrupt to the waiting mainframe after the required number of cycles for a given frame. The Vector General does the display, performing realtime rotate, pan and zoom.

22 ‘Conformational analysis and neuroleptics’ Tollenaere, J P Department of Theoretical Medicinal Chemistry, Janssen Pharmaceutical Research Laboratories, B-2340 Beerse, Belgium

Structure-Activity-Relationships (SAR) in the class of neuroleptics have been discussed several times over the last 15 years. Whereas the earlier studies mainly concentrated on the topology, pharmacological profile, the mechanism of action and clinical aspects, it is only recently that the topographical aspects or 3D structure of neuroleptics have been studied in a systematic way. During the last 10 years a rapid growth of the crystal structure determinations on neuroleptics was seen. In fact, at the end of 1972 no more than four crystal structures of neuroleptics were known. At the end of 1978 35 were already available. At the end of 1982 the detailed 3D aspects of the solid state conformation of about 60 neuroleptics are available to the medicinal chemist. This amount of data makes it possible in principle to analyse and compare the 3D anatomy of the various structural subclasses of neuroleptics.

Since it is now well established that most neuroleptics are conformationally flexible molecules, it is clear that one cannot solely rely on the conformation derived from X-ray determinations. It is of utmost importance to know all the energetically accessible conformations of a given neuroleptic or of a drug in general. As long as we do not know the conformation of a neuroleptic in its receptor environment and have as yet no means to determine this medicinal chemist’s ‘fourth’ aggregation state, we are forced to investigate the conformation in the three classical aggregation states viz. isolated, liquid and solid state. Conformational analysis of a drug molecule, however, is not an end in itself but rather provides a basis for answering the question of the possibly biologically relevant conformation. From the

inspection and analysis of all the energetically acceptable conformations of all molecules putatively interacting with the same receptor one could possibly propose a pharmocophoric pattern characteristic for the given class of compounds. This massive amount of data requires special handling techniques.

The aim of this contribution is to show how confo~ational analysis and the subsequent description and display of molecular structures using a computer graphics system can cope with this large amount of data and may lead to a better understanding of the intraclass structural similarities and differences of neuroleptics. Similar to other approaches to rational drug design, the study of the 3D aspects of drug molecules does not give a complete picture of a drug molecule. At least it may answer some questions which should be asked once the drug has reached its target area.

The computer graphics system built around a Tektronix 4054 microcomputer greatly assists the scientist in vizualizing molecules of biological interest. At this time the X-ray crystallographic data of some 1000 molecules are stored. Besides the Cartesian c~rdinates, each atom is further characterized by its type of hybridization and connectivity.

The system contains quite a large number of programs which allow storage, retrieval and display. It provides the user with the capability to input Cartesian coordinates via the internal coordinates (a flexible model building package which allows retrieval of fragments from a molecular fragment database consisting of frequenting used substructures approximately at the level of a physical Dreiding model set, will be implemented in the near future). Other options available or shortly available to the user include the determination of the absolute configuration (ABSCON), a best molecular fit routine (BMFIT), and the inversion from one enantiomer to the other (EXERT). The highly modular design of the whole system ensures an easy installation of new features to the already existing ones.

The empirical potential energy calculations are based on the summation of non-bonded van der Waals interactions, torsion potentials and H-bond potentials. The parametrization of the empirical constants was achieved by matching the empirical energies and the corresponding PCILO results. The bond rotation algorithm used in the conformational energy module offers the user three options to choose from. l a random scan of a user-defined number of

conformations to be explored 0 a grid scan in a user-defined conformational space

range e minimization procedure in a particular region of

conformational space according to the SUMT (Sequential Unconstrained Minimization Technique) scheme using the BFGS (Broyden, Fletcher, Goldfarb, Shanno) for the actual minimization

The whole software package is written in APL and runs on an IBM 3031 computer under MVS and TSO time- sharing system. The Tektronix 4054 microprocessor (BASIC) with 56 kbytes of RAM memory includes an additional 32 kbytes of dynamic memory dedicated to the creation and display of refresh objects independent of the 4054’s processor. The built-in matrix functions ROM pack allows global translation, rotation and

56 Journal of Molecular Graphics