Molecular mechanics models SYBYL

This chapter describes the basis of molecular mechanics models and introduces the SYBYL and MMFF force fields. It also compares and contrasts molecular mechanics and quantum chemical models. 

Molecular mechanics models differ both in the number and specific nature of the terms which they incorporate, as well as in the details of their parameterization. Taken together, functional form and parameterization, constitute what is termed a force field. Very simple force fields such as SYBYL, developed by Tripos, Inc., may easily be extended to diverse systems but would not be expected to yield quantitatively accurate results. On the other hand, a more complex force field such as MMFF94 (or more simply MMFF), developed at Merck Pharmaceuticals, while limited in scope to common organic systems and biopolymers, is better able to provide quantitative accounts of molecular geometry and conformation. Both SYBYL and MMFF are incorporated into Spartan. 

The MMFF molecular mechanics model provides an excellent account of C-N and C-0 bond distances. SYBYL also presents a credible account, although bond lengths for some systems are significantly in error. MMFF is clearly the better choice. 

Semi-empirical models are markedly inferior to all other models dealt with (except the SYBYL molecular mechanics model) for barrier calculations. Major trends in rotation barriers are often not reproduced, for example, the nearly uniform decrement in rotation barrier from ethane to methylamine to methanol. None of the semi-empirical models is better than the others in this regard. One the other hand, AMI is clearly superior to MNDO and PM3 in accounting for nitrogen inversion barriers. All in all, semi-empirical models are not recommended for barrier calculations. 

Theoretical models include those based on classical (Newtonian) mechanical methods—force field methods known as molecular mechanical methods. These include MM2, MM3, Amber, Sybyl, UFF, and others described in the following paragraphs. These methods are based on Hook s law describing the parabolic potential for the stretching of a chemical bond, van der Waal s interactions, electrostatics, and other forces described more fully below. The combination assembled into the force field is parameterized based on fitting to experimental data. One can treat 1500-2500 atom systems by molecular mechanical methods. Only this method is treated in detail in this text. Other theoretical models are based on quantum mechanical methods. These include ... 

SYBYL molecular mechanics is completely unsatisfactory for describing conformational energy differences in acyclic systems, and should not be employed for this purpose. On the other hand, the MMFF mechanics model provides a good account of all systems examined. In fact, the performance of MMFF is significantly better than any of the semi-empirical models, and in the same league as the best of the Hartree-Fock, local density, density functional and MP2 models (see discussion following). 

Similar comments apply to cyclic systems (Table 8-2). SYBYL molecular mechanics is completely unsatisfactory for establishing relative conformer stabilities, while MMFF appears to be quite well suited for this purpose. The only unsatisfactory case for the MMFF model is 2-chlorotetrahydropyran, where the noted preference for an axial chlorine (usually attributed to the anomeric effecF) is not reproduced. Caution should be exercised in the application of MMFF to carbohydrates where the anomeric effect may lead to significant conformational preferences. 

Figure 7.4. Upper Quadrants model for two possible transition states, TS I (left) and TS II (right) for an olefin (R O CR3 4) insertion into the Rh-H bond of RhH(CO)[(R,S)-BINAPHOS]. Lower Sybyl (Cache) representation of the molecular mechanics calculations of transition states, TS I (left) and TS II (right), for styrene (grey) insertion into the Rh-H bond of RhH(CO)[(R,S)-BINAPHOS] (black). Re-face binding of styrene to Rh is calculated to be lower energy than that of si-face binding to both TS I (by 7.1 kcal/mol) and in TS II (by 1.8 kcal/mol). In both structures, the enantioface selection seems to arise from the steric repulsion between the phenyl group of styrene and one of the naphthyls of (R,S)-BINAPHOS (marked with rectangles).

Model building, molecular mechanics (SYBYL, MM2, MM3), and ab initio (Hartree—Fbdc, Moller—Plesset, direct HF) and semiempirical (MNDO, AMI, PM3) molecular orbital calculations with and without solvent effects. Graphical front-end and postprocessor of die output. Elearon density and electrostatic plots. Interface to Gaussian 92. Convex, Digital, Hewlett-Packard, IBM, and Silicon Graphics versions. 

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