abuses of molecular mechanics: pitfalls to avoid

Abuses of Molecular Mechanics

Pitfalls to Avoid

Kenny B. Lipkowitz Indiana University Purdue University at Indianapolis, 402 North Blackford Street, Indianapolis, IN 46202'

Molecular mechanics (MM) is a nonquantum mechanical way of computing structures, energies, and some properties of molecules. The method and its underlying philosophy has been reviewed by this author in this Journal ( 1 ) and by others elsewhere (2). Because molecular mechanics treats electrons implicitly rather than explic- itly, molecular mechanics is a relatively fast com-

ABUSES OF MOLECULAR MECHANICS

Scientist - - Software

. Computational Artifacts . Potential Functions putational tool. This speed, along with its proven Comparing Results .Parameters reliability, has been recognized by both academic and industrial scientists as the method of choice Interpreting Results . Optimizers for computing structures and energies of medium-to-large-size molecules.

Historically, molecular mechanics was developed and used by a relatively small group of physical-organie chemists, These scientists wrote Figure 1. Molecular modeling typically involves a student or researcher (scien-

tisffuser) sitting in front of a graphics terminal of a workstation (software/theory), in- the programs, understood the theory they were puning commands, running the software, and interpreting the results. Accordingly, for and were of the Vmita- convenience, the abuses are categorized as those originating from the user and

tions of the techniques. In the early to mid- 80s those due to the and theory. several research a o u m provided ma~hica l user - A .

interfaces for these programs and'thepopularity of molecular mechanics erew raoidlv. What was - . - once a daunting task of assigning atom types and atomic Cartesian coordinates in molecular to~olopv files became . -. easy Moreover, because of the beauty of molecular graphics. modeline became alluring. Molecular modeling so& ware comp&ies evolved, wo;kshops to teach ~ c i ~ n t i s t s how to run those proprams proliferated, and the applica- . . tion of m&cular &e&anirsio pnhltm.; in mnuy areas ot' chemistry rapidly rook placr. .\lowadi~ys it is rare to find a . . chemistry department that does not have molecular modeling tools for research or for teaching.

This is a "good news"/"bad news" story. The applied theory of molecular mechanics, once only in the hands of true experts, is now developed for and used primarily by the nonexpert. These scientists and scholars are most suscep- tible to using the method improperly. Accordingly, the pur- pose of this tutorial is to inform the academic and research communitv about common ahuses and pitfalls to avoid when using molecular mechanics. The impetus for writing this paper came from a review article the author was asked . . to write on the application of molecular mechanics in organic synthesis (3). Of the 400 or so citations in that review, most had problems ranging from flagrant abuses of the technique to what might be called pet peeves. The . . ;iuthors of those papers, ltke researrhrr.; in othvr .;ubdiici- pllnes of the chemical science.;, simply do not have the time to become experts in molecular mkhanics but feel (right- fully) that much can be gained by using molecular mechanics to address questions in their research. Delineated here, as thoroughly as possible, are the many pitfalls to avoid when implementing molecular mechanics.

Abuses of Molecular Mechanics Figure 1 categorizes MM abuses. On the one hand, we

find the scientist who runs the software and interprets its

'e-mail: lipkowitz43chem.iupui.edu

1070 Journal of Chemical Education

results, and, on the other hand, there is the software along with its underlying theory that often is incomplete or has assumptions and approximations that the user should be aware of. Rather than select specific articles from the literature and impugn their integrity, general statements are made here that, when perusing the literature, you will be able to verify for yourself. We begin first with the software and the theory and then consider the molecular modeler. I t is important to tell you that much of what follows was gleaned from reading the literature, reviewing manu- scripts and proposals,.but, most came from my own experi- ences. I t is my intention to describe some of the mistakes I made so you will not get caught in the computational quag- mire that many of my colleagues and I have stepped into.

As used in this article, the tern software sometimes refers to the algorithms and sometimes to the concepts that serve as the theoretical underpinning of molecular mechanics.

Potential Functions

A n empirical force field (EFF) is a numerical recipe for reproducing a potential energy surface (PES). In the organic chemistry community, the terms "empirical force field" and "molecular mechanics" are synonymous. How- ever, molecular mechanics is not the same as empirical force field. Rather, MM uses an EFF. Indeed MM, like molecular dynamics (MD) and Monte Carlo (MC) simulation techniques, implement an empirical force field for what they need to accomplish. In MM the idea is to carry out simple energy minimizations to explore selected points on a potential energy surface.

In MM molecules are assumed to be held together by elastic or sticky forces that in turn are described by suitable potential energy functions. The analytic form of these PEF's usually are inadequate; i.e., they usually do not

harmonic function 8 0

6 0

- E! 40 . -

20 Y

b 0 >

-20

-40

0.6 0.8 1 1.2 1.4 1.6 1.8

b,A

Figure 2. Schematic of a Morse function and the related harmonic, cubic, and quartic potentials. When the bond length is increased beyond the point of the minimum, the harmonic potential rises too steeply. The cubic term corrects for the anharmonicity locally, but at longer distances turns and goes catastrophically to negative infinity. The quartic potential remains a good approximation over a relatively large range and always is attractive at large distances. Reproduced with permission from VCH lnc. (2b).

properly describe the true shape of the PES but only approximate it. Some EFF's, however, which have been well refined from years of research, approximate the true PES quite well; e.g., MM3. In Figure 2 are presented several functions used for bond stretching. Clearly, a s bond lengths become distorted anharmonicity becomes more important. Many popular force fields, especially those con- structed for biological molecules, use harmonic functions that are meant to reproduce the PES near the minimum only. What this means for the novice user is that force fields like AMBER and CHARMM, which use only harmonic stretching terms, are not well suited for assessing geometries of sterically congested molecules. For these systems substantial elongation of bond lengths are found and this will be underestimated by simple harmonic functions. Likewise, strained bonds in, say, cubanes and related polycyclics are not well described by such force fields. To avoid this, one should select a force field that better treats bond elongation as does the MM2 or MM3 force fields of Allinger or the CVFF of Hagler who uses a Morse function. Caution is still advised, however, because even though the potential may be adequate, the parameterization of the force field (vide infra) may not. The same argu- ments made here about bond compression and lengthening are, of course, applicable to bond angle deformations.

The inability to reproduce adequately a molecule's PES is especially prevalent in areas like inorganic and or- ganometallic chemistry. There, the multiple minima needed to describe adequately ligand directionality around a metal center are not well treated by existing organic force fields. Recent advances in this area of EFF are in pro- gress, however (4, 5) .

Furthermore, the potential functions that are selected for an EFF by force field developers are often chosen for computing speed (e.g., harmonic versus Morse function for bond stretching), or they are selected for convenience (e.g., 6-12 nonbouded functions). Additionally, most popular force fields are valence force fields. This terminology is derived from vibrational spectroscopy where, depending on what one includes or omits from the spectroscopic force constant matrix gives rise to one of several types of force

fields. Valence force fields include only the diagonal terms corresponding to bonded or valence interactions. By neces- sity then, one usually needs to supplement a molecular mechanics valence force field with nonbonded and cross- terms. These are often added aposteriori to make improve- ments between computed and observed vibrational fre- quencies and structure. Moreover, the term "force constant" often is used to refer to the restoring forces in a force field. A more suitable term is potential constant. Force constants refer to spectroscopic force fields and potential constants refer to MM force fields. Conseauentlv.

0 .

one cannot directly transfer a spectroscopic force constant into a MM force field. When s~eak ine or writinz about mo- - lecular mechanics, be sure to use the term "potential constant".

Finally, we need to be cognizant of how primitive most current EFF's are. They rarely include anisotropic functions, omit polarization effects, etc. For example, atoms in most molecules are not spherical, so one has to consider whether some sort of sph&ical average is appropriate, or whether the anisotropy needs to be taken into account. A good review of anisotropy in potential functions is that by Stone and Price (6). These and other effects like bond making and bond breaking functions (so-called reactive poteu- tials) are being developed now and soon will be implemented in molecular mechanics programs to represent better (model) reality.

Parameters

Evew em~irical force field has a set of ~arameters that - . is selected judiciously to reproduce a training set of experimental results (sometimes those ex~erimental results are derived from ab initio quantum tLeoty). Because every EFF is different. their Darameter sets are likewise different. For the everyday user, swapping and guessing parameters constitutes one of the major abuses of molecular mechanics. I t is common for molecular modelers to '%or- row" stretching or bending constants from, say MM2, for missing values in AMBER. MM's strength is based, in part, on "transferability." Transferability means the potential

Volume 72 Number 12 December 1995 1071

functions and their parameters that reproduce, for example, a G C bond length in butane, pentane, or hexane, will also reproduce the C-C bond length in a larger hydrocar- bon like polyethylene. In other words, within a given EFF, there is transferability between atoms in a similar molecular environment. A n EFF parameter set developed for n-alkanes simply will not work well for branched or strained alkanes. Transferability does not mean transferal of parameters from one EFF to another. I t is common, nonetheless, to find scientists making such exchanges. This is improper and constitutes a cardinal violation of MM protocol.

Part of the MM parameterization process involves the electrostatic term. Some EFF developers like Allinger use - bond moments; whereas, others use atom-centered charees to model electrostatic interactions. These charees and lbond dipoles are adjusted during the paramete& tion to reproduce experimental data for a variety of molecular properties. I t is common, however, for users to select their own atomic charges derived their own way. The most common practice nowadavs is to use charges that are derived from eiectrostatic fitti& to high quality ab initio molecular electrostatic potential surfaces. Not everyone does this and, consequently, one often finds MM calculations on the same molecule with the same force field but with very different charges giving rise to very different results. Most EFF's developed for biopolymers seem to have reasonable electrostatics because thev reproduce solvation energies fairly well. For some force fields like MM2iMM3, solvation is a problem. Bond moments usuallv are fitted to give correct molecular dipole moments. Because several bond dipoles can be varied different ways to get the same total dipole, solvation energies are not accurate.

Another abuse of EFF parameters involves the nonaddi- tivity of functional groups. While MM2, for example, is good for C=C and for C-OH, one cannot combine these parameters for the corresponding enol, C=C-OH. If functional groups are 2 2 bonds apart, i t is best to reparameter- ize that as a new group.

Parameter quality is an important, but often neglected, issue. Alarge number of empirical force fields (EFF's) have been developed over the vears for use in molecular mechanics, moiecular dynamics, and Monte Carlo simulations. Each force field has a uniaue set of parameters and a set of potential energy functions. The quality of the potential functions together with the quality of the associ- ated parameters determines how well the EFF can reproduce a molecular potential energy surface. While the potential functions generally remain unchanged from moltwl(, to rnoltudt , ctmaln parameters may hc n w d d for one n~olecule but not another. The ones needed deoend on the molecular topology file and atom types making up the molecule beine studied. Because the number of atom - types and the possible arrangements of those atom types is so large, only a small fraction of all possible combinations have been parameterized

Many molecular modeling programs contain parameters published in the literature. The modeler is advised that ;hen using a force field to go back to the original literature to see precisely what molecules were used in the parameterization data set. This point is most crucial. Qpically, EFF parameters are developed only for a small number of molecules in a data set, and, more often than not, for a very narrow range of structural types. These parameters coulb. inadvertentlv be used bv the unwary molecular modeler for all classes of moleckes containing that functional group even though the parameters were meant to reproduce only a narrow subset of those molecules. It is easy to transgress the boundary between legitimate and illegiti- mate use of EFFH because of this.

In the literature one finds a bimodal distribution of oa- rameter quality. On the one hand is the author of the force field who makes monumental efforts to minimize the error between computed values and a wide range of experimental results. In this regard, note that paralnet(!rirati(,n often involvrs f i ts to detobases that mieht ~ncludc molt!ru- - lar structure, vibrational data, heats of formation, molecular dipole moments, heats of sublimation, or rotational barriers from NMR or other spectrosco~ic measurements. Well tested, robust, high quality are the result.

On the other end of the spectrum is the occasional molecular mechanics user who needs to compute a molecular structure. If the requisite parameters are missing, it is common to make up a set by extrapolation, interpolation. or just by guessing.-~ome users wili create their own data- bases of experimental properties and derive a set of Da- rameters. 1; contrast to.the EFF developers who use la&e data sets for their ~arameterizations. these users often have small data sets; e.g., two, three, or four molecules pulled from some source such as the Cambridge Structural Database, making the resulting parameter set less robust than desired by most users. Moreover, many of the parameterization~ are fitted onlv to molecular structure. Use of these parameters for computing, say, vibrational frequen- cies may be meaningless.

Some of the authors who publish these parameters ac- knowledge this and list caveats and potential hazards other users should be aware of. As a user you should be cognizant of these issues. Because many MM programs do not describe where their parameters come from, this may not be possible. I t is ill-advised to use parameter sets a t face value; many of them were developed poorly. Lists of published parameter sets exist (71, and you should refer to them to see what those parameters were intended for and to assess the quality of the parameters you are using.

Finally, a subtle but important point about parameters concerns their suitability for use in your These parameters were developed to reproduce. as well as oossible. the EFF's training set of compounds. For example; if those ~arameters were ontimized for bulk solution nronerties. . . they may not provide meaningful results on small clusters. ~ikewise, for calculations may not be suitable for MD calculation though thev probablv are close. " . For certain, room temperature, atmospheric pressure parameters are not good for high temnerature. high nressure - , - . simulations. An example o?how bne may inadvertently abuse molecular mechanics is to study thigas phase clui- terine of small molecules around aromatic hvdrocarbons with; force field parameterized for bulk prop&ties. Anice examole of this is reported bv Dvkstra and Zwier (8) who " " compared the experimental structures and stabilities of h e n i e n e - ( ~ z ~ ) z - ~ i with computed values from OPLSITIP~ and OPLSITIP~ and from Dykstra's MMC model.

Optimizers

Given an initial set of atomic coordinates, molecular mechanics programs attempt to position the atoms so that all of the restoring forces on those atoms are zero. For all but the simplest molecules, this is not possible and all molecules have some internal strain. Nonetheless. geometry , - optimizers are developed to seek the nearest energy minimum on the molecule's PES. The issue of conformational analysis is described later. Here we point out that manv energy minimizers give misleading or'false results. For example. some alzorithms look s i m ~ l v for a stationarv noint . " 0 .

(zeio &adient).-~representative example of this involves a dialog between several users on the Ohio State Computa- tional Chemistry List (CCL). An excerpt is given.


Neil Ostlund points out the dangers of simply accepting MM calculations without careful consideration of what the force- field is doing. He gives biphenyl as an example where MM2 for instance treats the torsion angle for the single bond between the rings using the same atom types as the aromatic bond in a benzene ring. Net result a flat biphenyl.

I was a little amazed at this, so I tried optimizing biphenyl in MACROMODEL that has MM2 as one of its choices with the following result: . Starting with a flat biphenyl-energy optimization

gives a flat biphenyl. . Starting with a 10-degree twist-energy optimization gives a 37.8-degree twist. Starting with an 89-degree twist-energy optimization gives a 37.8-degree twist.

The conclusion is that except for starting out flat, the MM2 force field will twist the bond to 37.8 degrees a very acceptable result. But how could this be ifit uses the same parameters for the single bond as an aromatic bond?

So I examined the force constants for the bonds by printing out the .mmo file. Sure enough the program is smart enough to rec- ognize that the benzene ring is a special structure with a VZ torsion parameter of 9.2; whereas, the single band (containing the same four-atom types) has a V2 of only 1.7. I am glad to see that MM2 as implemented by MACROMODEL isn't all that bad.

The problem here, along with the ensuing dialog, is that the discussion focuses on the force field parameterization when the issue really involves the optimization method! A tutorial by Schlick explains how good the various optimizers are and which ones should be used (9). I t is common for novices andlor the unwary to report energy minima that are artifacts of the optimizer rather than a description of the PES.

Vendors

This is a cautionary note to those users who rely exclu- sively on purchased software. The vendors inadvertently promote abuse. Low quality parameter sets and inadtt- quate potential functions arc masked by glitzy promuti~ms. "Ruve; beware" is the o~erative ~ h r a s i h i r e . In contrast to - ~~ " - - ~ ~ ~~~ ~ ~

equipment vendors who provide specifications on signal- to-noise ratios for spectrometers, software vendors do not usually provide specifications; you will not find root mean square (rms) deviations for heats of formation, molecular dipole moments, rotational barriers, etc., so be careful and do not blindlv use their software. There are a few cases where the vendors have discussed their EFFs in peer-reviewed iournals, but this is not common. Test i t out first on molecufes whose properties are known to see if i t can per- form to your level of expectation.

Why do vendors inadvertently promote abuse? The answer is economics. Basically, if company Asells an MM program for inorganics, companies B, C , and D will come out with a comparable program whether i t is ready or not. I t is a very competitive world in that regard, and the commer- cial software companies often are forced to release prema- ture or overextended products. Be careful. The vendors could and should be more aware of the pitfalls their nov- icelnonex~ert clients mav fall into. Vendors should flag - possible errors or potential abuses. Searching for the global minimum of a 500-residue peptide. for example, is 1'11-advised and should be flagged. ~ ikewise , cautibn& notes about untested or tentative parameters should be pointed out for the user during an-application. Unfortu- nately, we, the users, often are lulled into believing the

of our calcula&ons are always good, but the market prevents vendors from telling you otherwise.

The Scientist You and I are human, and we tend to make mistakes.

These mistakes and errors can be minimized; that is the

point of this article. Much of what we do with molecular mechanics is improper or outright wrong, and in this sec- tion we delineate common failures of the scientist who is using the software.

Computational Artifacts

Man-made errors pervade computational chemistry One of the most common errors of scientists is to equate mini- mizationleeometrv ootimization with conformational ~. , . analysis. MhI, with most optimizers, seeks the nearest en- e rw minimum on the molt~culr's I'ES. not the most s t a l h

-0

structure. Some chemists still are disappointed when boat cvclohexane does not convert soontaneouslv to the chair form upon geometry optimization. Most of us, however, understand that one needs to explore a PES to understand molecular dynamics, and many of us rely on the dihedral driver method for scanning through conformational space. Use of these dihedral drivers constitutes another abuse of molecular mechanics. Torsion scanning with partial minimization gives lopsided curves and sometimes discontinuities. Even with full relaxation, discontinuities are found for stericallv coneested molecules. These discontinuities - ~ - ~~~ ~~~ " - are computational artifacts due to rotating around only one or two bonds; whereas, driving around several is re- quired. The same pathway should be found when making a transit from one region on the PES to another and then back again. The principle of microscopic reversibility must hold.

Another abuse of MM by the scientist is the failure to establish convergence in conformational searches. Most scientists inadvertently carry out limited conformer searches, es~eciallv when applyine MD methods. In the .. . - systematic search'method, a common misconception is that just because every individual torsional angle in a molecule was sampled over its entire range, that all of conformational space was sampled. Furthermore, the quality of the search depends on the dihedral angle increment. A good tutorial on how to sample conformers for small and medium-size molecules exists (10). Later the merits of the "global energy minimum" will be discussed.

Related to the idea of finding minima on a molecule's PES is the selection of a n energy minimizer. Above we pointed out that some algorithms find false minima. Re- lated to this is the scientist who introduces artifacts by using the wrong optimizer a t the wrong time. For example, steepest descents methods.inefficiently search for the minimum on flat surfaces. Another artifact is to compute the wrong Boltzmann distribution of conformers by prema- turely ending the enerm minimization. I t is surprising how much lower in energy some conformers become by changing optimizers or by extending the number of steps in the minimization with the same EFF. In this regard, the user should be cautioned to assess critically the default settings toggled by most vendors.

Another major abuse of MM is the omission of a molecule's environment. I t is not uncommon, for example, for researches to discover that the second or third most stable conformer found in a gas-phase calculation becomes the most stable one in a crystal lattice. Most of us cany out molecular mechanics calculations to understand con- densed phase chemistry. In this regard the most common artifacts introduced bv the scientist are leaving out solvent, especially when polar functional groups are present, omission of counter ions, and, variable selection of dielectric constants. ~ m i s s i o ~ of solvent effects is perhaps the most prevalent and insidious artifact scientists introduce into their MM calculations. I t is common to find calcnla- tions on systems having two or more polar functional groups in vacuo when experiments are done in solution. Without solvent (continuum or explicit treatments), re-


sults become dominated by electrostatics that unrealisti- cally favor hydrogen bonding, salt bridging and the like. Also omitted are counter ions. The ion atmosphere surrounding a molecule can be as important as the molecule itself if the molecule has ionized groups, and this needs to be accounted for in a viable way. It is amazing to watch practicing bench chemists who, cognizant that their results subtly depend on solvent polarity, pH, or ion concen- tration, sit in front of an odor-free, quiet graphics terminal and c a m out molecular mechanics calculations on a eas phase ion!

Finallv. reeardine mainlv MD simulations. we point out that ap&oxikatio& intended to speed up calcul~ions can be disastrous. These a~~roximat ions include using united atoms, (this also applies to MM), employing no&onded cutoffs that are far too small, equilibration time periods that are far too short, using too few solvent moiecules, andlor too small a periodic box surrounding the molecule being studied.

Comparing Results

To what should the results of MM calculations be compared? The most common error encountered is one of terminology concerning MM energies. First, steric energies # strain energies # heats of formation. These terms have very different meanings, but, unfortunately, they are used interchaneeablv. Second. and most problematic, is that raw MM &ergi"es are not free euer&es. I t is common for scientists to equate MM2 steric energy differences with free energy differences determined by some chemical or spectroscopic probe.

Related to this is the assumption that the lowest energy conformer is most abundant. Illustrated in Figure 3 is a representation of a potential energy surface with two minima. The larger width of the higher energy minimum- leading to flexibility compared to the lower energy one-could result in a lower free energy. The question of the significance of the "global minimum" rears its ugly head in various chemical subdisciplines like crystallography where the structure in the lattice mav not be the most stable, and in the pharmaceutical industry where the phar- macoloeicallv active conformer need not be the lowest en- - " ergy one.

The most common error made bv svnthetic chemists when using MM involves the curt in-~ammett principle. Briefly. for a simple two-conformer system where each con- formergives risi to different products as in eq. 1 when k ~ , z and k2.1 m k~ and kz ,

the relative amounts of product formed are independent of their rcl,~tive populatio~s, and they depend on the free cn- e r ~ ~ e s of their corresponding rransition stiites. Indeed, it IS

well established that a com~ound can react exclusivelv in a conformation other than that which predominates in the ground-state equilibrium distribution. Omission of the Curtin-Hammett principle is one of the major abuses of MM bv bench chemists who compare product distributions with conformer populations.

Interpreting Results

Assuming one has carried out a successful MM calculation. avoidine all the aforementioned ~itfalls. internreta- tion'of the r&lts can be challenging i n d pr~hlern&ic. A common abuse of MM by scientists is to misinterpret or overinterpret their results. For example, one often finds extensive discussions of results in the literature where

Figure 3. A schematic representation of a potential energy surface with two minima. Because of vibrational motion, the broad minimum of a higher-energy conformer may contain enough vibrational entropy to reduce its free energy below that of a lower-energy conformer.

with some experimental observation. Small energy differences in MM are meaningless. Allinger's best MM3 parameterization~, for instance, are often reported with rms deviations for heats of formation of -0.4 kcal mol-'. This is stellar, but not all EFF's can do this well (see the discussion about lack of vendor specifications).

Another issue involves component analysis. One of the assumptions of MM is that the total energy is a sum of contributing terms; i.e.,

E = E,+EB+E,+Evdw+. . .

where E, is stretching energy contribution, EB is the bond angle contribution, E, is the torsional energy contribution, EVAW is the Van der Waal's enerw contribution. and the . . . means othcr terms may contrib"Fe to the total energy While most MM lorce lields will find axal mcthvlcvclohexnnc to be approximately 1.7 kcal mol-I less stable than the equatorial form, thev do so for different reasons. The total enerm is -. what is important, nrlt the nlmponent energies. A general rule ol thumh is to use three different KF'F's from threediffer- ent authors. If their components are quantitatively similar, then you may be correct in validating sour hypothesis.

~ n b r h e r abuse in\.ol\res what rn1g.h; be caiied ..self-fulfill- inrc pronhecles." The first of these i s to have preconceived - - . notions. For example, if one intends to search'for a binding site on a complex receptor where it is thought (presumed) to exist, this search is often done at the expense of other possible sites. lho much user intervention that relies on "chemical intuition" can be dangerous. Let the computer do the search for sou and see what i t finds. If the results are counter-intuitive yet within the realm of chemical knowledge, you may have provided an alternative way of thinking about things.

The second self-fulfilling prophecy involves false predic- tions. This is claiming a true "prediction" but using essen- tial experimental data to enable that prediction. Agood ex- amnle of this is in crvstal nackine nredictions where the - z scientist takes the experimental X-ray conformation to predict ~ a c k i n e arraneements. Molecular mechanics cal- culatiois with-such "brcu~ar reasoning" often gives the right answer.

Pet Peeves

A varietv of other nitfalls to avoid are presented here. What is written alsb could be warning; for molecular modelers using other comnutational tools as well. The first is "force field gashing." ~ L i s is where an author tunes up his or her force field for a particular functional erouo. makes comparisons with an"'off the shelf' program and then denierates the latter's aualitv. On more than one oc-

small energy differences computed by MM are consonant


casion, I have reviewed papers where, for example, com-

parisons were being made to MM2, but, because MM2 did not have parameters for that functionality, the authors had the audacity to transfer parameters from their own force field for use in MM2 to illustrate how poorly MM2 performs!

Another problem to avoid involves publication of results. Many researchers report their results as "MMY calculations when, for instance, they really mean MM2' or MM2* or MMX. This is misleading for the rest of us and puts an unfair workload on the original EFT author who invariably receives calls of complaints that their published results are wrong. Re- lated to this is publishing papers that have incomplete experimental sections. One must provide the parameters used if they are not standard, indicate the version of the program implemented, values of cutoffs used, dielectric constants used, ete., so that we, the readers, can reproduce that experi- ment, if needed. Finally, avoid publishing graphs that do not provide anv additional information (eswciallv prevalent are k1) rrajecthit~.; and grirphicdl representation; of molerules tha t are cwnfusinp or dilficult co interpret. 'lhrst, an, admit- tedly pet peeves,but they are pitfal& to avoid when using molecular mechanics.

Summary Molecular mechanics has evolved rapidly a s a reliable

computational tool for determining molecular structures and energies. Many assumptions and approximations are

made in molecular mechanics which most users are not aware of. What once was in the hands of experts who understood these assumptions and who were cognizant of the limitations of the theories, is now made ava;lable for the everyday consumer who is prone to making errors and fall- ing into computational pitfalls. This tutorial addresses these problems. When used properly molecular mechanics is a very powerful predictive tool. I t is the author's hope that by bringing these common errors and pitfalls to the fore many novice and unwary users will avoid common traps that would otherwise jeopardize their results.

Literature Cited 1. Boyd. D. B.;Lipkowitz K B. J. Chem. Educ. 1982,59,269. 2. (a1 Bowen. J. P, Allinger, N. L. In Rwiews in Computational Ch~mLsLry ,Val 2.

Lipkowitz, K B.; Boyd, D. B.,Eds.;VCH: New York, 1991; Chapter 3. (bJ Dinur,U.: Haeler A. T. Reuimos in Comolrfolio~l Chemisirv :Vd 2. Chanter 4. - . . . . ~. ~~

3. L3pkowits.K B. Cham. Re". 1993.93. 2463. 4. Rapp6, A. K; Casewit, C. J.; Colwell, K. 8.; Gaddard 111. W. A ; Ski& W. M.; Jh.

Chem. Soc. IsB1,114, 1W25.\ 5. Landis, C. R.; Root, D. M.: and Cleveland, T I" Rsuiews in computatio"a1 Chrmis-

t n Vol. 6: Liokowitz. K. B.: Boyd. D. B.. Eds.: VCR: New York. 1995: Chanter 1. . . 6. Stone,A.J.; Price, S. L. J. Phys. Chem. 1988.92, 3325. 7. (a1 Lipkowitz, K B. QCPE Bulletin 1992, 12(1l, 611. (hl Osawa, E.; Lipkowitz, K

B. JCPENeusleller 1993, 5111.3-23. ("1 Osawa, E.; Lipkowitz, K 8. InRsviews in Computational Chemistry. Vol 6: Lipkowitz. K B.; Boyd, D. B., Eds.: VCH: New ""& >oat. a""e"A:" 7 .".", .""" ,..pp-.. ..

8. Augspurger J.; Dykstra, C.; 2wier.T. J Phys. Chem. 1988,97,980. 9. Sehliek, T In R d e w s in Computoloml Chemistry, Vol. 3: Lipkowitz, K B.; Boyd,

D. B., Eds.; VCH: New York, 1992; Chapter 1. 10. Leach,A. R. InReuiews in computntionoi chemistry, vo1.2: Lipkowitz, K B.: Boyd,

D. B., Eds.: VCH: New York, 1991: Chapter 1.


abuses of molecular mechanics: pitfalls to avoid

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