An On-Line Guide to
Molecular Modeling - Part 1

Dr. Howard Black - Department of Chemistry - Eastern Illinois Univ.

    As recently as 15 years ago, using computers to model reactions, calculate reaction energies and steric parameters, and calculate, with great visualizations, the energetic minima for a structure, was mainly the area of physical chemists and a few strange organic chemists with a weird attraction for mathematics. During the intervening years, though, many software packages have become available - from free to quite expensive and sophisticated (but still running on a PC) - and any synthetic or medicinal chemist who still doesn't utilize these tools is seriously behind the times.

    This short tutorial is designed to provide an introduction to computational chemistry as applied to organic reactions, in two totally different environments.  Part 1 deals with PC-based calculations, where you use a program installed on a PC to execute and display the results of molecular calculations.  Part 2 is an introduction to server-based calculations, where you access a site where everything is done on the site's computers; these services are generally free, which are the only ones that will be discussed.

PC-Based Molecular Modeling

    There are a number of commercial software packages that are used for this purpose; probably the best known are Spartan® Chem3D.  Spartan, supplied on many CDs that accompany organic chemistry texts, is a standard energy minimization and energy calculation package; Chem3D, however, is capable of much more diverse calculations, algorithms, visualizations, and file formats supported.  Thus, the intention of Part 1 is to familiarize you a little with CambridgeSoft's great Chem3D-Ultra program.  Chem3D does things that, until very recently, were thought to require the power of a mainframe; the great increase in both hard disk size/speed and RAM, combined with elegant algorithms reducing the complexity of the calculations, has enabled virtually any required calculations, including ab initio (totally quantum mechanical) programs.  Depending on the complexity of the molecule being studied, some calculations can take some time, but I've yet to run one that required more than about 15min.

    With Chem3D, the structure is best drawn with a chemical drawing program, then copied/pasted into the modeling program.  The best free application is called ISIS Draw, by ACD Labs, Inc.  To get yours, just click the logo to the right.  Requires a (free) short registration, and they won't drown you with spam or sell your address to a gazillion other vendors.

Take a Look at ISIS/Draw
    It's fairly self-explanatory, but a few comments will save you some time. First, let's take a look at the tool bars across the top. The shapes across the top are probably the only templates you'll need. Down the left column is a series of commands, but there's much more than that. Any command with a small arrow in the lower right (the great majority) is just one of a series, which can be visualized by right-clicking on the icon. You'll be amazed at how much was crowded into such a small, *free* program! (By the way, the icon at the bottom of the list involves "AutoNom", ACD's nomenclature program. Just select your structure (with the topmost icon) and click AutoNom, and within 3 seconds, you'll have the IUPAC name!

Pasting Into Chem3D following be a Quick Minimization
    Once you're happy with your structure, just select it and copy it to the clipboard, then go to Chem3D and paste it in. Usually, it doesn't look too good at first, so it's common to do a quick conformational minimization using the molecular mechanics protocol. Take a look at the
Chem3D command bars. In the middle of the bottom row is an icon called MM2, which stands for molecular mechanics, and is a shortcut to an energy minimum. MM is the fastest of the computations, and is a great way to start. As it's calculating, look at the "output" area (across the bottom of the screen) - you can see the energy falling as the model moves around, seeking the structure with the lowest energy.

    Now that you've got a decent-looking model, you can do whatever it is you came to do. To get a better quality minimization, you can go to the "Calculations" button, and choose from one of the other available methods, the most typical of which are MOPAC (semi-empirical, i.e., a mixture of MM and quantum mechanics), and GAMESS (totally ab initio, or quantum mechanical).

A Hidden Hint About Calculating Huckel Charges and Surfaces
    The best way to get to know the program is just to play around with it a lot, and use the great help files (F1). Some things are not as well documented as they could be - for instance, if you wanted to calculate Huckel charges and/or create Huckel surfaces, you'd go to the "Surfaces" button, right? Wrong. First you go to Calculations, where one of the pull-down options is "extended Huckel", from which you can choose "charges" or "surfaces". You have to calculate the parameters before you can show the result, see? It may be documented somewhere, but it's escaped me so far.

    The navigation buttons: The bottom row begins with several icons to govern what your mouse does. The arrow is for selecting certain structures or atoms. The hand is for moving objects, which needn't be selected - just get the hand near the structure. The curved arrow, next, is the most common mode, which allows rotation of the structure through all three dimensions simultaneously. The Up/Down arrows make an object larger or smaller. The four-way arrow moves individual pieces, like atoms, bonds, etc.

    The upper row of icons is self-evident until you get to the purple thermometer (it's actually a double bond, but it had me fooled..). From here, you select the model type (lines, wireframe, ball&stick, space-filling). After the background color icon, you can choose what type of stereo you want - either the silly-looking red/blue goggles, or the useless polarity filter. Then come two icons for 3D effects - "perspective" and "depth fading". The former makes distant things smaller than nearer ones; the latter dulls the light on more distant things. The two can be combined to give a look that's unusually silly. Then come two icons for showing two axes, two for atom labels or numbers, and finally you can switch to full-screen mode or make the molecule rotate.

The Output of Energy (and other) Calculations
    All calculations are done in the "Output" area right below the Chem3D window (if you can't see it, it may be minimized, but it's definitely there). Fortunately, it never discards any calculations until you leave the program; by scrolling up you can retrieve any calculation done during the whole session - even those leading to lousy results.

Saving Structures as either Vector or Image Files
    One of Chem3D's strengths is the incredible number of file formats it can both read and write. I've never actually counted them, but there must be 50 formats - from common visualization formats like .pdb (Protein Data Bank), .mol (MDL-generated images), and .cdx (ChemDraw); to more obscure ones like .int (internal coordinates), .xyz (Tinker MM3 Input), and .rdl (Rosdal). It can also save the actual images, in all the usual formats (gif, jpg, bmp, png, tif). If you want to prepare an annotated image (add writing or something else to it), the best thing is to save the image in png format (it's the most general), and then use a graphics program (FireWorks, PhotoShop, Paint, etc.) to add the text.

The End!
    Chem3D is installed on most of the computers in the computer lab, as well as the lab computer. I know there's a certain energy of activation when deciding to learn a new thing, but you'll have this program down in no time, and find yourself playing with it for hours, so - about that Eact - get over it and have some fun!!