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Metode semiempiris yang paling terkenal adalah metode AM1 (Autin Model 1) dan PM3 (Parametric Method 3).

Hasil dari kedua metode ini tidak dapat dibandingkan tetapi keduanya memiliki kecenderungan hasil yang relatif sama (Marcel Dekker Incorporation, 2004). AM1 Metode AM1 dikembangkan oleh M.J.S. Dewar et al., di Universitas Texas, Austin. Dalam pengembangannya, metode ini didasari oleh perhitungan MNDO (Modified Neglect of Diatomic Overlap) untuk memperkirakan integral dua elektron tetapi menggunakan perhitungan lain yang dimodifikasi untuk tolakan inti-inti atom. Perhitungan modifikasi ini menghasilkan gaya interaksi non-fisik yang seperti pada interaksi van der Waals. Perhitungan modifikasi ini mengharuskan suatu model diparameterisasi ulang, yang terbawa oleh tekanan partikular pada momen dipol, potensial ionisasi dan geometri suatu molekul (Ramachandran, et al., 2008). Dengan adanya perubahan pada fungsi teoritis tolakan inti atom, metode ini mampu memprediksi ikatan hidrogen dengan sangat baik. AM1 sangat berguna untuk molekul organik yang tersusun oleh atom-atom dari kolom 1 dan 2 dalam tabel periodik, tetapi tidak cocok untuk logam transisi. Metode AM1 dapat digunakan untuk menghitung sifat elektronik, optimasi geometri, energi total dan panas pembentukan dari suatu molekul. Dengan demikian secara umum, metode AM1 merupakan metode yang paling akurat dan merupakan metode yang paling baik untuk mengumpulkan informasi kuantitatif (Hypercube Incorporation. 2002). Metode AM1 dapat digunakan untuk menentukan struktur dan distribusi elektron untuk senyawa besar dan sangat besar. Metode AM1 terbukti dapat diaplikasikan pada polimer glisin yang terdiri dari 19995 atom dan molekul RNA yang terdiri dari 6304 atom. Metode AM1 juga dapat digunakan pada struktur yang relatif kecil seperti ibuprofen. Hasil kristalografi ibuprofen memiliki kesamaan dengan hasil perhitungan energi potensial dengan metode ini (Marcel Dekker Incorporation, 2004). PM3 PM3 yang dikembangkan oleh James J.P. Stewart ini merupakan parameterisasi ulang dari metode AM1 yang mengabaikan tumpang tindih dua atom yang berbeda. PM3 berbeda dnegan AM1 hanya dari nilai parameternya. Parameter PM3 diperoleh dari perbandingan sejumlah sifat molekul hasil komputasi dengan hasil eksperimen dengan jumlah yang lebih banyak dan beragam. Perhitungan ini menghasilkan interkasi tanpa ikatan yang lebih sedikit dibandingkan dengan AM1. PM3 terutama digunakan untuk molekul organik dan juga untuk logam-logam transisi seperti Ti, Mn, Fe, Co, Ni, Cu, Zr, Mo, Rh, Pd, Hf, Ta dan W (Hypercube Incorporation. 2002). Sama halnya dengan AM1, metode PM3 juga dapat diaplikasikan pada molekul besar. Metode ini telah terbukti dapat diterapkan pada optimasi geometri plasminogen yang terdiri dari 1226 atom (Marcel Dekker Incorporation, 2004). Perbedaan asumsi tolakan inti menghasilkan perbedaan hasil perhitungan antara metode AM1 dan PM3. Ikatan hidrogen yang dihasilkan oleh PM3 kurang baik jika dibandingkan dengan AM1 tetapi mampu menjelaskan interaksi hidrogen-hidrogen non fisik. Namun PM3 memiliki tingkat akurasi prediksi termokimia PM3 lebih baik dibandingkan dengan AM1 (Marcel Dekker Incorporation, 2004). Menurut Marcel Dekker Incorporation pada tahun 2004, tidak ada perbedaan signifikan antara metode AM1 dan PM3. Perhitungan konformasi energi pada 1000 atom dengan kedua metode ini tidak menghasilkan perbedaan yang signifkan tetapi PM3 memperlihatkan total kesalahan yang relatif lebih kecil dibandingkan dengan AM1.

The most popular semiempirical methods are Austin Model 1 (AM1) [7] and Parametric Model 3 (PM3) [8]. The results produced by different semi-empirical methods are generally not comparable, but they often do reproduce similar trends. Apparently, there is no significant difference in the average errors for these four methods. It has to be noted that the reference set of MNDO, AM1, and PM3 is almost twice as large as the MSINDO reference set. Finally, we have tested two popular semi-empirical methods, AM1 [52] and PM3 [53].For conformational energies of molecules with around 1000 atoms, semiempirical methods are still the only feasible QM alternatives. The difference between these two methods was not statistically significant, but PM3 gave a slightly lower total error in the test and was therefore used in all comparisons AM1 AM1 is generally the most accurate computational method included in HyperChem and is often the best method for collecting quantitative information. PM3 is functionally similar to AM1, but uses an alternative parameter set (see PM3 on page 156). (halaman 132)

MINDO/3, MNDO, and AM1 were developed by the Dewar group at the University of Texas at Austin. This group chose many parameters, such as heats of formation and geometries of sample molecules, to reproduce experimental quantities. The Dewar methods yield results that are closer to experiment than the CNDO and INDO methods (Halaman 134)

Many problems with MNDO involve cases where the NDO approximation electron-electron repulsion is most important. AM1 is an improvement over MNDO, even though it uses the same basic approximation. It is generally the most accurate semi-empirical method in HyperChem and is the method of choice for most problems. Altering part of the theoretical framework (the function describing repulsion between atomic cores) and assigning new parameters improves the performance of AM1. It deals with hydrogen bonds properly, produces accurate predictions of activation barriers for many reactions, and predicts heats of formation of molecules with an error that is about 40 percent smaller than with MNDO. Problems still exist with AM1. Treatment of phosphorus-oxygen bonds is inaccurate, nitro compounds are still too positive in energy, and the peroxide bond, for example, is still too short. In many cases, PM3 is an improvement over AM1. (halaman 156)

An improvement of the MNDO method and one of the most accurate methods. Useful for organic molecules containing elements from long rows 1 and 2 of the periodic table, but not transition metals. Possibly better than MNDO for compounds containing both nitrogen and oxygen. Calculates

electronic properties, optimized geometries, total energy, and heat of formation. This is an SCF method (halaman 299)
Austin Model 1. A semi-empirical, SCF method for chemical calculations. One of the MOPAC methods [Stewart, J.J.P., J. Comp.Aided Molec. Design 4(1):1-108, 1990]. An improvement of the MNDO method. Useful for organic molecules containing elements from long rows 1 and 2 of the periodic table, but not transition metals. Generally the most accurate method included in HyperChem. Calculates electronic properties, optimized geometries, total energy, and heat of formation. (halaman 789)

The Austin Model 1 (AM1) method, developed by M. J. S. Dewar and coworkers, takes a similar approach to MNDO in approximating two-electron integrals, but uses a modified expression for nuclear-nuclear core repulsion. The modified expression results in non-physical attractive forces that mimic van der Waals interactions. The modification also necessitated a re-parameterization of the model, which was carried out with a particular emphasis on dipole moments, ionization potentials, and geometries of molecules. While this allows for some description of the hydrogen bond, other deficiencies, such as systematic over-estimates of basicities, remained unsolved. Also, the lowest energy geometry for the water dimer is predicted incorrectly by the AM1 model. On the other hand, AM1 nicely improves some properties, such as heats of formation, over MNDO. (halaman 141) CNDO and INDO results are less accurate than minimal basis set ab initio methods. Hence these methods fail to compute accurate binding energy. Dewars approach was to treat only valence electrons.Most of the theories such as theMINDO, MNDO, AM1, PM3, SAM1, and MINDO/d methods use a minimal basis set of valence Slater type s and p AOs to expand valence-electron MOs. A comparison of the heat of formation with MNDO, PM3, and AM1 methods has been made in Table 7.1. The CNDO method is crude, fast and can do second row elements. The INDO method is better for first row elements, while theMINDO3 andMNDO methods are more reliable. The AM1 method is better for estimating H bonds. The PM3 method, developed from AM1, includes more main-group elements. For ordinary molecules, AM1 or PM3 are probably the best to try. Semiempirical methods are highly useful for better geometry optimization than force fields, especially geometries for molecules including atoms which are not parameterized in a force field. It makes the qualitative prediction of IR frequencies and the total electron density surface for graphical display. They are not really good enough for reaction energies and equilibrium constants; even quite low level ab initio methods are better for energetics.(halaman 148-149) In the Austin model 1 (AM1), s = p. Parameterization with compounds from H, B, Al, C, Si, Ge, Sn, N, P, O, S, F, Cl, Br, I, Zn, and Hg have been made. (halaman 148) Austin Model 1. A semi-empirical quantum chemical Hamiltonian originating from theM.J.S. Dewar group. The quality of the AM1 results in many cases is beyond the simpler ab initio results and is superior to the MNDO method especially in the description of hydrogen bonds, when compared to other all valence electron methods (halaman ) This method is widely applied for the structure determination and electronic structure calculation of large and very large organic systems. Some of the most impressing calculations in recent semiempirical applications are the AM1 energy calculations on

a 19995-atom polymer of glycine and a 6304-atom RNA molecule [118] where the MillamScuseria conjugate-gradient density-matrix search was applied to replace conventional matrix diagonalization. The molecular electron density calculated with AM1 has been used as a basis for the parameterization of simple electrostatic field models that are used to obtain quantitative structure activity relationships (QSAR) for a series of singly substituted amines as well as para-substituted benzoic acids and other bioactive substances [119,120]. The conformational flexibility of the Ibuprofen molecule has been analyzed by crystallographic database searching and AM1 potential energy calculations [121]. A combined AM1 and HF study has been carried out for the interaction of anhydrotetracycline, the major toxic decomposition product of the antibiotic tetracycline, with aluminum [122]. In this study, a perfect agreement of semiempirical and ab initio calculations was observed demonstrating the reliability of the AM1 method for structural and energetic properties of organic molecules. A systematic conformational analysis of anhydrotetracycline, a toxic decomposition product of the widely used antibiotic tetracycline, has been carried out with AM1 [123]. The results were used to explain the toxic effects of the anhydrous derivative.

PM3
PM3, developed by James J.P. Stewart37, is a reparameterization of AM1, which is based on the neglect of diatomic differential overlap (NDDO) approximation. NDDO retains all one-center differential overlap terms when Coulomb and exchange inte-grals are computed. PM3 differs from AM1 only in the values of the parameters. The parameters for PM3 were derived by comparing a much larger number and wider variety of experi-mental versus computed molecular properties. Typically, non-bonded interactions are less repulsive in PM3 than in AM1. PM3 is primarily used for organic molecules, but is also param-eterized for many main group elements (halaman 134)

PM3 can also be used to study transition metal (tm) compounds; new parameters include the following elements Ti, Mn, Fe, Co, Ni, Cu, Zr, Mo, Rh, Pd, Hf, Ta and W

PM3, developed by James J.P. Stewart, is a reparameterization of AM1, which is based on the neglect of diatomic differential over-lap (NDDO) approximation. NDDO retains all onecenter differen-tial overlap terms when Coulomb and exchange integrals are com-puted. PM3 differs from AM1 only in the values of the parameters. The parameters for PM3 were derived by comparing a much larger number and wider variety of experimental versus computed molecular properties. Typically, nonbonded interactions are less repulsive in PM3 than in AM1. PM3 is primarily used for organic molecules, but is also parameterized for many main group ele-ments.(halaman 305) A reparameterization of AM1. PM3 differs from AM1 only in the values of the parameters. The parameters for PM3 were derived by comparing a much larger number and wider variety of experi-mental versus computed molecular properties. Typically, nonbonded interactions are less repul-sive in PM3 than in AM1. PM3 is primarily used for organic molecules, but is also parameterized for many main group elements. This is an SCF method (halaman 299)

The ParametricMethod 3 (PM3) model, developed by James Stewart, uses a Hamiltonian that is very similar to the AM1 Hamiltonian, but the parameterization strategy is different. While AM1 was parameterized largely based on a small number

of atomic data, PM3 is parameterized to reproduce a large number of molecular properties. In some sense, chemistry gave way to statistics with the PM3 model. A different parameterization, and a slightly different treatment of nuclear repulsion allows PM3 to treat hydrogen bonds rather well, but it amplifies non-physical hydrogen-hydrogen attractions in other cases. This results in serious problems while analyzing intermolecular interactions (methane is predicted to be a stronglybound dimer) or conformations of flexible molecules (OH is strongly attracted to CH3 in 1-pentanol). The accuracy of thermochemical predictions with PM3 is slightly better than that of AM1. The PM3 model has been widely used for the rapid estimation of molecular properties and has been recently extended to include many elements, including some transition metals.(halaman 141)
Stewart re-parameterized the values to generate the PM series. That derived from AM1 is known as the PM3 (Parametric method 3). In the PM3, one-center electron repulsion integrals are parameterized by optimization. The core repulsion function takes only two Gaussian functions per atom. In PM3, compounds containing H, C, Si, Ge, Sn, Pb,N, P, As, Sb, Bi, O, S, Se, Te, F, Cl, Br, I, Al,Ga, In, Tl, Be,Mg, Zn, Cd, and Hg have been parameterized. (halaman 148) Parametrized Model 3. PM3 is a version of the AM1 method reparametrized by J.J. Stewart. On the whole PM3 gives better estimates of the heat of formation than AM1. PM3 has been used in drug design, for example, on the effect of dinitrosubstitution on the methylation reaction of catechol and endogenous catechol derivatives catalyzed by catechol O-methyltransferase (COMT) [124], where the implications of the derived reaction mechanism to the design of COMT inhibitors are discussed. PM3 has been modified for the calculation of very large systems. Examples are the geometry optimization on the 1226-atom Kringle 1 of plasminogen [125] with a conjugate-gradient technique replacing matrix diagonalization. A series of epibatidine analogs and their positional isomers bearing an 8-azabicyclo[3.2.1]octane moiety has been described in a combined experimental and PM3 study [126,127]. The oxidation decomposition of 2,4,6-tri-tert-butylphenol and related compounds was investigated by calculating the reaction enthalpies with PM3 [128] in a study of the cytotoxic activity of these compounds. Recently, the electronic structure of a mutagen, chloroimide 3,3-dichloro-4-(dichloromethylene)-2,5pyrrolidinedione, has been calculated for a correlation with its known bacterial mutagenicity value [129].

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