Mouse + micro = molecular model

188

T I B S 1 3 - M a y 1988

129,313-370 19 de Rey-Paiihade, J. (1921) Bull. Gen. Ther. CLXXII,606--607 20 de Rey-Pailhade, J. (1926) Bull. Soc. Chim. Biol. 9,512-522 21 Heffter,A. (1908) Med. Naturwiss. Arch. I, 81-103 22 Arnold, V. (1911) Z. Phys. Chem. 70, 300325 23 Ouastel, J. H., Stewart, C. P. and Tunnicliffe,H. E. (1923)Biochem. J. 17,586-592 24 Johnson, J. M. and Voegtlin, C. (1927) I. Biol. Chem. 75,703-713 25 Stewart, C. P. and Tunnicliffe, H. E. (1925) Biochem. J. 19, 207-217 26 Pirie, N.W. (1962) Proc. R. Soc. Set. B 156, 306-311 27 Voss, W., Guttmann, R. and Klemm, L. (1930)Biochem. Z. 220,327-341 28 Harington, C. R. and Mead, T. H. (1935)

Biochem, J. 29,1602-1611 38 Gurin, S. and Clarke, H. T. (1934) J. Biol. 29 Hunter, G. and Eagles, B. A. (1927)J. Biol. Chem. 107,395-419 Chem. 72,147-166 39 Harris, L. J. (1929)J. Biol. Chem. 84, 29630 Hopkins, F. G. (1927) J. Biol. Chem. 72, 320 185-187 40 Pirie,N. W. and Pinhey, K. G. (1929)1. Biol. 31 Hopkins, F. G. (1929) ,'. Biol. Chem. 84, Chem. 84,321-333 269-320 41 Bergmann, M. and Zervas, L. (1932) Bet. 37 Kendall,E. C., MeKenzie, B. F. and Mason, Dtsch. Chem. Ges. 65,1192-1201 H. L. (1929)J. Biol. Chem. 84,657-674 42 duVigneaud, V. and Miller, G. L. (1936) Y. 33 Kendall, E. C., MacKenzie, B. F. and Biol. Chem. 116,469-476 Mason, H. L. (1929) Staff Meetings of the 43 Larsson,A., Orrcnius, S., Holmgren, A. and Mayo Clinic 4,264--266 Mannervik, B. (eds) (1983) Functions of 34 Kendall, E. C., Mason, H. L. and McKenzie, Glutathione; Biochemical, Physiological, B. F. (1930)J. Biol. Chem. 88,409-423 Toxicological and Clinical Aspects, Raven 35 Kendall, E.C., Mason, H. L. and McKenzie, Press B. F. (1930)J. Biol. Chem. 87, 55-79 44 Dolphin, D., Poulson, R. and Avramovic,O. 36 Nicolet, B.H. (1930)J. Biol. Chem. 88, 389(eds) (1988) Giutathione in Coenzymes and 393 Cofactors, John Wiley& Sons 37 Grassmann,W., Dyckerhoff,H. and Eibeler, 45 for other reviewssee Annu. Rev. Biochem. 52 H. (1930)Z. Phys. Chem. 189,112-120 (1983)-54(1985)

Microfile Mouse + micro = molecular model Alchemy T M Molecular modelling software for the IBM (PC, AT, XT or compatible) Tri-

subset of other Tripos offerings which run on the upmarket Evans & Sutherland graphics terminals.

p o s Associates Inc.*, 1986. US$750 commercial/S450 educational users.

Specific requirements

A molecular modelling kit is one of the essential requirements for all chemistry and biochemistry undergraduate courses. At the research level, however, molecular modelling is increasingly being undertaken using more sophisticated computer graphics-based systems. Typically these systems have highly specialized hardware for realtime rotation of the molecules, and are priced well outside the budget of most individual research groups. Tripos Associates, with their Alchemy program, aim to provide such a modelling system at a price which is more within the budget of the research scientist. AlchemyT M is designed to run on the IBM PC range of microcomputers (and compatibles) and to provide the same type of functionality as expensive dedicated systems. Tripos claim that their program performs the task of a computerized 'Dreiding model kit', with facilities for building and displaying wire-frame and solid molecules. The program is distributed by Evans & Sutherland, of which Tripos is a subsidiary, and is in effect a budget priced

Although designed to run on the ubiquitous IBM PC, the hardware requirements to run Alchemy are quite stringent - an enhanced graphics display (EGA) with a full 256K RAM is mandatory, as is the use of a mouse (Microsoft or Mouse Systems, Inc. only). The program is quite strict about which mouse it uses; I tried using the popular Logitech mouse with no success. The only hard copy devices supported are the Hewlett-Packard range of plotters; no output can be printed on a dot matrix printer. Tripos strongly recommend the use of a numeric coprocessor to speed up the mathematical calculations involved. In addition they recommend a hard disk drive, which is quite essential as the Alchemy files occupy 2MB (in total) of disk space. After testing the program on various computer configurations, I strongly advise the use of at least an AT level computer; XT type computers (8088 processor) run the program very slowly, even when assisted by a numeric coprocessor. These requirements mean that only a small proportion of 'IBM compatible' systems are actually suitable for running Alchemy.

* Tripos Associates, lnt:., 6548 Clayton Road, St Louis, MO 63117, USA. Distributed by Evans Installation and copy protection & Sutherland through their offices in: Munich, Installation of Alchemy is quite simFRG; Cambridge, UK; Palaiseau, France. ple. The system is provided on seven I~ 1988,ElsevierPublicationsCambridge 0376-5067188/$02.00

floppy disks, which are simply copied onto the hard drive. In order to run the program, however, it is necessary to insert one of these disks into drive A: so that the copy protection mechanism can check that the original program is being used. This form of copy protection is one of the most benign in use, but can be somewhat irritating for the user of the program. It is understandable that Tripos should wish to protect their investment, but this type of copy protection detracts from the utility of a program. For example, it makes the program inappropriate for use in a teaching environment, where disks are frequently misplaced or damaged, and where it is essential to be able to make backup copies. Rotation in real time

In use Alchemy is reminiscent of programs which run on much larger machines. Molecules are displayed as wire-frame images in the main part of the screen, and are coloured to show different atom types. Options are selected from a menu at the right of the screen using the mouse. Selection of these options requires rather precise positioning of a tiny cursor (which could be improved upon). Extensive help is available, but in practice this is rarely required as the options are largely self-explanatory. Molecules can be built up from pre-defined functional groups or from constituent atoms, and the finished product saved to disk. The displayed molecule may be rotated and translated in real time. Bearing in mind the limitations of the hardware this

TIBSI3-MayI988 rotation is handled very well. The smoothness of the rotation is dependent upon the speed of the computer used - with an IBM XT compatible there is a noticeable delay between each view of the molecule being displayed. On an AT machine the rotation is quite smooth, and at the top of the scale on a fast 80386 based machine a delay is not noticeable unless a large (> ---50 atoms) molecule is being manipulated. In each case, however, effective use is made of double buffering (the updated molecule is drawn in a second screen buffer, and the display switched to this screen only when the drawing is complete) to ensure that no flicker is visible. As well as a wire-frame image it is possible to draw the molecule in space-filling representation. This works quite well, albeit a little slowly, but is for display purposes only as it is not possible to plot out a picture of the finished solid object.

Steric contacts and depth perception Alchemy works well when existing molecules are retrieved from disk and displayed. It is less convenient to use when a new molecule needs to be constructed. In practice it is often far quicker to use a model building kit than it is to use Alchemy. For example, rotation of a bond in order to remove bad steric contacts is one of the most common actions during model building, and is extremely easy using physical models. Alchemy requires the following steps: (1) pick the four atoms which define the torsion angle to be redefined by the bond rotation, (2) enter a new numerical value for this torsion angle in degrees, and (3) inspect the molecule to determine whether the torsion angle entered has removed the unfavourable interaction. This process is unnecessarily difficult; even experienced model builders have trouble specifying appropriate numerical torsion angle values (ironically a physical molecular model is of great assistance here!). It would be greatly advantageous to have the option of interactive rotation about any given bond, ideally with a continuous readout of the current torsion angle value. The problem of building the most appropriate conformation is made far worse by the limitations imposed by the display system. The problem concerns depth perception on a two dimensional screen it is impossible to tell the front of an object from the rear unless presented with some visual clues. Dedicated workstations overcome this either by 'depth cueing',

189 using increased intensity for objects closer to the obse~'er, or by 'flash stereo' utilising special viewing spectacles. The only provision in Alchemy is to display side-by-side stereo pairs, which may be used to give 'cross-eyed' or 'relaxed-eyed' stereo. This works relatively well for some users; others find such images impossible to visualize correctly. This lack of apparent threedimensionality in the displayed object is the major drawback of the Alchemy software. To be fair it is mainly imposed by the limited hardware, however it should be possible to include a red/green stereo option (and provide suitable viewing spectacles) and/or make use of the extended palette of the EGA to give a depth-cued monochrome image (for example using several different intensities of blue). Energy minimDation One advantage that computer-based modelling packages have over physical models is that it is possible to calculate atomic distances and angles. This is achieved very simply in Alchemy by selecting the appropriate option from the menu and then choosing the atoms required using the mouse. A further advantage of sophisticated programs is the ability to optimize molecular geometry by energy minimization. Alchemy has provision for such minimization to remove bad steric contacts, or to optimize bond geometry, for example after constructing a cyclic system. In use, I found that the success obtairied

depended upon the starting geometry. One pa~icularly alarming feature of the algorithms used occurred when minimizing a bad contact involving an aromatic ring, where there is a tendency for the flat aromatic system to become puckered during the minimization. This reflects limitations in the calculations, and leaves one sceptical about the validity of any conformation arrived at using this minimizer. In summary Alchemy is a difficult product to assess. Given the limitations of the display hardware the program copes admirably. However, the limitations are sufficient to discourage serious use for constructing large molecules. It is also often far simpler to visualize features of molecular geometry from a physical model. One purpose to which Alchemy is very well suited is teaching; the program pro~ides an excellent demonstration of the application of computer-assisted molecular modelling. The only drawbacks are that the hardware requirements are suca that few systems are suitably equipped to run the product, and that the method of copy protection used may be a problem in a teaching environment. ROBIN J. LEATHERBARROW

Department of Chemistry, Imperial College of Scienceand Technology, South Kensington, LondonSW72AY, UK.

Modellingdynamicbehaviour Biograph by Garrett M. Odell and Lee A. Segel,

Cambridge University Press, 1987. £30.00/$39.50 (xiii + 242 pages) ISBN 0 521 33973 1. (Associated disc for IBM PC or AT, 256K RAM, maths co-processor ISBN 0 52133974 X.) In a recent review (TIBS 12, 389) of software designed to aid mathematical modelling of dynamic processes, the reviewer (C. G. Morgan) commented that it was a package in need of a textbook. Biograph is a graphical modelling package, aimed at mathematically orientated undergraduates or postgraduates, and designed to complement an existing textbook, Modeling

Dynamic Phenomena in Molecular and Cellular Biology by Lee Segel (Cambridge University Press, 1984). Indeed,

the link is so strong that the Biograph manual contains an errata list for the book! Although the program could be used independently, the constant references in the manual (and to a lesser extent in the program) make it very desirable to have the book handy. The equations which Biograph can solve are restricted mainly to the differential and finite difference equations dealt with in the book. This covers a wide range of examples, including quasi-steady-state enzyme kinetics, chemostat behaviour, cAMP and slime-moulds, developmental biology and ecological systems. In addition, some general equations are provided, as is a study of the glycolytic oscillator. An equation to be studied is entered by loading an example file which contains specimen parameters. These par-