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computer series, 134
JAMESP. BIRK Arizona State University Tempe, A2 85281
So You Want To Do Molecular Modeling? A Consumer's Guide to Desktop Modeling Programs for the Macintosh J. Philip Bays
Saint Mary's College, Notre Dame, IN 46556 The rapid developments in microcomputer hardware have brought computational chemistry and molecular visualization to the desktop. The problem for many of us has been the lack of software that is relatively easy to use and offers the functions necessary to meet our research and classroom needs. The purpose of this article is to provide a broad overview of five Macintosh software packages. Each provides a tool with which the user can construct and view molecular structures, perform force field calculations, and aualitativelv visualize the snatial relationshius between reactive fundionalities in related structures. students will be able to use these nackaees in lieu of model sets. combining the features of'framework, ball-and-stick, and CPK models. In doing so, they will miss "handling the molecule", but they will be able to examine routinely the beauty and complexity of biochemical structures, many of which are far too complicated for normal model building. With an instructor's guidance to interpreting computational results, students can more quantitatively examine conformational energy relationships in small molecules. Alchemy 111, ~ e m e s i s ' , P C - M O ~MacMimic4, ~~, and Chem3D Plus5 will be reviewed. Table 1 provides a summary of features. For full implementation, all require a model of the Mac I1 family with reasonable memory (2-4 Mb) and color capability. Although Chem3D functions for model construction on all versions of the Macintosh, a Mac I1 is required to implement color display and molecular mechanics and dynamics computations. All of the programs are multifinder compatible. Alchemy I1 is also available for the IBM PC. PC-Model is a small systems implementation of Model and is available for the IBM PC/XT/AT, PSI2, and RISC 6000 a s well a s the Silicon Graphics Personal Iris and the Sun SPARC station. While it does not implement the Macintosh interface a s well a s the other programs, the format is consistent across all of the systems for which it is available. For this review the programs have been examined using a Macintosh IIcx with math coprocessor and 5 Mb of RAM. Space constraints prohibit a complete description of each product. Thus, I will 'Tripos Associates, Inc., 1699South Hanley Road, Suite 303, Saint Louis, MO 63144. 20dord Molecular. Terrapin House, South Parks Road, Oxford,UK OX1 3 I-I-. R~ -. . . .
'Serena Software, Serena Software, Box 3076, Bloomington, IN 47402-3076. %star Software AB, Research Park IDEON, 5-22370 Lund, Sweden. 'Cambridge ScientificComputing, Inc., 875 Massachusetts Ave., Suite 41, Cambridg*, MA 02139. 'For example, AutoMac I l l or QuickKeys.
focus on structure construction, display and manipulation, and molecular mechanics calculations. Structure Construction Nemesis, PC-Model, and Alchemy contain single model windows in which several models can be constructed and manipulated. Chem3D and MacMimic allow for construction of multiple structures in any of many model windows. The number of simultaneous structures possible is simply memory limited (see Table 1). The programs employ three basic methods for the construction of structures. The most common, used by all five programs, is best labeled in the words of the T r i p s promotional materials a s "Electronic Dreiding Models". Structures are assembled from preexisting fragments. The programs differ primarily in the method used to access the fragments. Nemesis fragments consist of geometry optimized molecules (methane, cyclohexane, benzene, etc.) located in an extensive set of folders. The fragments are connected by designating the hydrogens on each to be replaced by a bond. Alchemy I1 uses this folder method for molecular fragments while atoms are obtained from the Atoms menu selection. MacMimic is similar to Alchemy I1 except t h a t commonly used fragments (methyl, phenyl, etc.), atoms, and hybridization options are conveniently located on a desktop palate. PC-Model places everything on the desktop including atom types, commonly used molecular fragments, biomolecules, and a large array of metal atoms. Chem3D uses element, atom, and substructure windows that can be opened and scrolled alongside the model display window and from which "pieces" can be selected. A fragment can also be cut from one structure and pasted onto another. I n the course of preparing this review, I have spent many hours constructing molecular models. The authors of MacMimic and Chem3D have implemented keystroke equivalents for the commonly used menu selections; the others have not. This is a particular problem with both Alchemy I1 and Nemesis. While this may seem to be a minor consideration, I developed a case of "mouse wrist" which required that I refrain from using the computer for about a week. Although I have tested them only with Alchemy 11, I have found menu modification programs to be helpful in this regard.= I encourage each vendor to pay close attention to the implementation of keystroke equivalents in all future updates. My general evaluation is that Alchemy 11's implementation of the fragment construction method probably will be easiest for beginning students since it most resembles the molecular models with which they may have had some experience. On the other hand, MacMimic has the most conVolume 69 Number 3 March 1992
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Table 1. Program Features Alchemy II Nemesis PC-Model MacMimic Chem3D
Alchemy II Nemesis PC-Model MacMimic Chem3D Version Academic Price
1.2 $650
1.01 £250
4.0 $400
1.0 $1000
Plus 3.0 $595
System Requirements
Macintosh Model Memory Matti Coprocessor
Mac II
Mac II
Mac ll
Mac II
2Mb yes
4Mb yes
4Mb yes
1.5Mb yes
Atom Types Sketch facility Mnemonic entry User definable atom types
34 no no
21 nod no
60 yes no
43 no no
yes
no
yes
yes
no
no
yes
no
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
no
yes
yes
no
no
yes
no
no
no
no
yes
Mac Ila
Structure Construction
Output File Types MM2 SYBYL CSSR PDB MOPAC MacroModel ChemJD Alchemy PlCT
Editing Single atom movement Angle alteration Dihedral aneration Bond Length alteration Chirality Determination Stereochemical inversion - o n chains and on rings - at ring fusions Undo Command
Printing Options
ves
Color laser printer Copying to Clipboard Energy Minimization
Display b
b
Atom Limit 1000 296 b b b Molecule limit 10 Framework rotatable rotatable rotatable rotatable rotatable static rotatable rotatable Ball and Stick static nod Space Fill static static static no rotatable no Dot surlaces no rotatable static nod Model Windows Resizable Model Window no nod yes yes yes Depth Queing Stereoyes yes yes yes yes viewing Fitting and yes yes yes yes yes Docking Animation no no no no yes sequences
'Structure construction is possible on any Mac version with a math coprocessor. tom and molecule display or minimization limit is memory limited. %as& upon the MM2(87) force field with expanded parameter sets
210
MM2 SYBYL CSSR PDB MOPAC MacroModel Chem3D Alchemy ChemDraw
Journal of Chemical Education
Force Field Atom Limit Dihedral Searching (angles) Dihedral Fix Batch Operation Multitasking Dynamics
Tripos 0
COSMIC 125 5
MMX 296 2
MM2(87) 100 2
no no
nod no
yes yes
yes yes
noe no
no
no no
no yes
yes no
yes yes
b
no
Energy Output
Heats of formation Dipole Moment Standard Entropy
no
no
yes
yes
no
no
no
yes
yes
no
no
no
yes
no
no
Documentation (pages)
170
125
119
337
94
"Option will be included in future update 'It is possible to fix atoms in space, but not to do a formal dihedral search.
venient and elegantly designed presentation for the practicing chemist. A second method of structure construction, the "sketch" approach, is available in both PC-Model and Chem3D. One simply uses the mouse pointer as a pencil to draw a structure. As im~lementedin PC-Model the user must also designate whiih atoms are behind or in front of the screen plane, and then must add hydrogens with a click of the mouse to complete the structure. The resulting model must be enerev minimized to establish correct bond lengths and angles. When sketching with ChemSD, the atoms are added a t each step of the drawing process with correct bond lengths and with hydrogens attached. This slows the drawing Drocess considerably but results in a more reasonable-&a1 structure thadnsually requires fewer computational cycles to optimize. Furthermore, one can directly and convenientlycut and paste structures that ,~ it is critical have been sketched in C h e m D r a ~though that stereochemical assignments be clearly and unequivocally designated if they are to be understood by Chem3D. The final construction method is emdoved . " onlv in Chem3D. The user simply types a mnemonic representation of a molecule that is interpreted correctly by the program for display. For example, typing 'Ph" gives rise to a benzene rine: enterine P ~ C H ~ C H ( C H ~ C H ~constructs CHI the correct complete structure in the-model window. The oromam is able to translate these commonlv understood k n ~ m o n i c sinto substructures and a compiete model. I have found this to be the quickest and most convenient method for model construction, provided one correctly remembers the mnemonics. PC-Model and Chem3D have the widest range of fragments and atoms. These are most conveniently presented in PC-Model that has both biofragment and metal display options. The former makes available the common nucleic acid building blocks, amino acids, and monosaccharides. Unfortunately, for the uninitiated the abbreviations can be confusing.. The metals menu contains 39 metals. It takes only a few minutes, using the instructions provided, to construct and enerw minimize a model of ferrocene. In the product, the i r G i s shown coordinated to each of the 10 carbons. Ferrocene. also. is constructed easilv usine Chem3D. In t h i s case the iron is shown bonded to "dummy" atoms in the middle of each of the cyclopentadiene rings. While few of the Chem3D metals have been parameterized for enerev minimization, it is Dossible to o ~ t i mize the structural geometry, an option not available in the other programs. Alchemy comes with six metals prrdefined (K, Na, Fc, LI, Al, Ca,. No instructions are included concerning how to construct structures using these metals. It is not clear that it is possible to 'coordinate" instead of "bond," and I was unable to determine how to build ferncene. MacMimic is advertised to handle the construction of molecules containing any atom type in the periodic table from hydrogen to uranium. This is accomplished by specifying the element and hybridization. Unfortunately, the latter is limited to monovalent, sp, sp20rsp31tis not clear how to build ferrocene. Nemesis comes with one generale New atom t w e s can be ized metal atom t v ~ ~redefined. user defined in aliif tge programs though insirictions for doine so are not ~rovidedfor Nemesis. Althoueh this can be useful for model construction, specificationoTthe meaningful parameters for molecular mechanics computation is much more difficult. The fragment libraries in all of the programs can be expanded by the user. This is sometimes a n interesting "chemical" exercise. For example, building cyclohexanenitrile in Nemesis requires appending an ethyne to the ring, deleting the terminal hydrogen, and "retyping" the terminal carbon as a nitrogen, the computer modeling eqniva-
-
lent of a transmutation. Likewise. a nitro erouo is derived from a formaldehyde fragment b i retyping thk hydrogen as an oxveen and the carbon as a nitroeen. Nevertheless. once co&ucted and saved in the fra&ent library, thesd groups are available for future use. It is likely that the user will want to edit structures. Here there are significant differences among the programs. Only PC-Model and Chem3D allow individual atoms to be moved while maintainine bond connectivities. This makes it easy to convert chair k d boat cyclohexane usine the mouse oointer to move a carbon. In PC-Model the hydrigens do not'follow the carbon, but can be deleted easily and re-added to be in the correct position; in Chem3D the hydrogens accompany the movement of the carbon. In the other programs, the conformational change requires that a cylcohexane ring bond be broken, torsions changed to achieve the boat geometry, and the ring bond reformed. This is often frustrating and is undoubtedly why the fragment libraries contain both chair and boat cyclohexane fragments. With the exception of Alchemy 11, the programs allow for atom retyping. By simply pointing and clicking at an atom, it can be changed to another atom type. For example, to convert cyclohexane to piperidine one need only choose a nitroeen and then ~ o i nand t click on the a ~ ~ r o ~ r irine ate carbon. With ~ l c h e m I1~this interconversion is not so c o g venient. The carbon must be deleted. a nitroeen added to one end of the resulting chain, and the ring r&osed. Since my students and I are prone to making mistakes, an "Undo" command would have been useful in the structure construction and editing processes. Only Chem3D and MacMimic activate this option in the edit menu. A further editing issue relates to stereochemistry In the current version of Nemesis, it is possible to determine the absolute configuration at a chiral center, but it cannot be conveniently changed, though this facility is promised in a future update. In the other programs, inversion of the stereochemical center is accomplished automatically with the mouse pointer. However, only in PC-Model is this inversion ~ossiblea t the bridgehead of a ring (ex.. - svstem . - cis to trans decalin).
.. .
Display and Manipulation of Structures
. - .
Each Droeram oermits the user to resize a structure and to rotate it about the x, y, and z axes. The rotation is accom~ l i s h e dwith Alchemv's "eadeet box". buttons in MacMimic Hnd Nemesis, either""ro
