8224
J. Phys. Chem. 1996, 100, 8224-8229
Conformations of 1,2-Dimethoxyethane in Gas and Solution Phase from Molecular Mechanics and Monte Carlo/Stochastic Dynamics Simulations D. Jeremy Williams and Kathleen B. Hall* Department of Biochemistry and Molecular Biophysics, Washington UniVersity School of Medicine, St. Louis, Missouri 63110 ReceiVed: September 5, 1995; In Final Form: December 27, 1995X
The conformations and energies of 1,2-dimethoxyethane (DME) are estimated using molecular mechanics and Monte Carlo/stochastic dynamics (MC/SD) simulations. The torsional parameters of the Amber* and OPLS* force fields were modified to reproduce high-level ab initio data describing DME conformer energies in the gas phase. Predicted conformer populations from gas-phase molecular mechanics and simulations are in agreement with theoretical calculations and with previous electron diffraction data. For simulations in chloroform and aqueous solution an implicit solvation model (GB/SA) was used. The GB/SA treatment gives the TGT as the most populated conformer in aqueous solution, providing the major contribution to the observed gauche effect around the C-C dihedral. Significantly, the energy of the TGT conformer is lower than that of the TTT structure in solution, and it is stabilized relative to the TGG′ conformer. These results are compared to previous work in solution and in vacuo and with ab initio results.
Introduction Over the past two decades 1,2-dimethoxyethane (DME, CH3OCH2CH2OCH3) has been the focus of theoretical and experimental studies aimed at characterizing its conformational properties in gaseous as well as condensed phases.1-5 However, the conformational preferences of DME, and in particular the magnitude of the C-C gauche preference (“gauche effect”), remains somewhat controversial. Theoretical work done by several groups has demonstrated that both a reasonably large basis set (with diffuse and/or polarization functions) and electron correlation correction are necessary to accurately represent the relative energies of the DME conformers.6,7 These ab initio results predict that the all-trans (TTT) conformer is the most stable in the gas phase but give somewhat different energies for the TGT and TGG′ conformers (two other significantly populated conformers at room temperature) relative to the TTT conformer. Experimental NMR results describing the solvent and temperature dependence of the vicinal CH2-CH2 coupling constants of DME were analyzed in terms of a single gauchetrans equilibrium, leading Viti and co-workers to calculate a vapor-phase stabilization of 0.42 kcal/mol for the gauche state.1 Abe and co-workers have also estimated the magnitude of the gauche-trans energy difference from an analysis of the 1H1H and 13C-1H NMR vicinal coupling constants within the framework of a rotational isomeric state (R.I.S.) model.4,8 On the basis of interatomic distances obtained from electron diffraction measurements, Astrup concluded that at room temperature, gas-phase DME exists as a mixture of several conformers.3 The conformer populations estimated from the electron diffraction work differ somewhat from those calculated from the R.I.S. analysis of coupling constants, but both studies give a gauche C-C fraction of about 70%. Several authors (Tasaki and Abe,4 Podo et al.,2 Andersson and Karlstro¨m,5 and more recently Liu et al.9) have concluded on the basis of theoretical and experimental studies that polar media stabilize the gauche C-C dihedrals but have a significantly smaller effect on the C-O gauche-trans equilibrium. * Correspondence to this author. X Abstract published in AdVance ACS Abstracts, April 15, 1996.
S0022-3654(95)02581-0 CCC: $12.00
On the basis of these studies, a consistent conclusion is that the anti conformer of DME (TTT) is the most stable in the gas phase at moderate temperatures. The molecule still displays an overall gauche preference about the C-C bond because of the magnitude of the TGT and TGG′ populations however, and this “gauche effect” is enhanced by polar solvents. In contrast, the conformation about the C-O (O-C) bond is predominantly trans and does not change significantly upon solvation. It has been suggested that certain aspects of gas-phase DME conformers are not adequately handled in molecular mechanics schemes without ad hoc modifications.10 Others have concluded that an accurate prediction of DME structure in polar solvents may not be possible using a continuum solvent description.5,9 In this study, we report molecular mechanics calculations and mixed Monte Carlo/stochastic dynamics (MC/SD)11 simulations of DME in the gas phase, and in solution using the GB/SA12 solvation model (analytical continuum model). The O-CC-O and C-O-C-C torsional parameters of the Amber* and OPLS* force fields have been adjusted to bring them in line with high-level ab initio data.6,7 We demonstrate that the GB/ SA model in conjunction with the modified force fields allows accurate modeling of the DME conformational equilibrium in aqueous solution, and at a fraction of the computational cost of an explicit solvent simulation. Methods Simulation and Molecular Mechanics Methodology. All simulations were performed with the MacroModel and Batchmin V4.5 molecular modeling programs16 using the mixed Monte Carlo/stochastic dynamics (MC/SD) protocol.11 Each simulation consisted of a 1 ns preequilibration period followed by a 5 ns production run. A 1 fs time step and a frictional coefficient (γ) of 2.5 ps-1 was used for the stochastic dynamics, with a nominal simulation temperature of 300 or 315 K. The MC portion of the MC/SD algorithm applied random torsional rotations between 0 and 180° to all rotatable bonds except methyl carbon-oxygen bonds at the termini. A 1:1 ratio of SD to MC steps was used. All nonbonded cutoff distances were set at 25 Å, greater than the largest molecular dimension, and the entire pair list was used in the evaluation of nonbonded © 1996 American Chemical Society
Conformations of 1,2-Dimethoxyethane
J. Phys. Chem., Vol. 100, No. 20, 1996 8225
TABLE 1: Torsional Parameters for the Modified Force Fields Amber** dihedral
a
X-C-O-X X-C-C-X O-C-C-O O-C-C-O O-C-C-O C-C-O-C C-C-O-C C-C-O-C a
TABLE 2: Energies of DME Conformers and Barriers Relative to the TTT Conformer conformer ab initioa ab initiob Amber*c Amber** OPLS*c OPLS**
OPLS**
Vn (kcal/mol)
n
Vn (kcal/mol)
n
1.272 1.647 0.183 -3.264 4.270 0.424 -0.680 1.410
3 3 3 2 1 3 2 1
1.260 1.818 0.202 -3.510 4.560 0.420 -0.119 0.010
3 3 3 2 1 3 2 1
X stands for any atom type.
derivatives. The Amber* and OPLS* force fields were used in conjunction with an implicit water model (GB/SA analytical continuum model).11-15 Chloroform and water parameters were used in the condensed phase work with both solvent polarization and surface area derivatives updated at each time step. During the production phase, distances (C1-C6) and dihedral angles (C1-O2-C3-C4, O2-C3-C4-O5, C3-C4-O5-C6) were accumulated every 10 time steps at resolutions of 0.1 Å and 5°, respectively, and 5000 snapshots of structures were saved. Simulation convergence was determined by monitoring (1) the potential energy stability, (2) the dihedral angle distributions (e.g., equal population of +/- gauche torsions of a given dihedral angle), and (3) by demonstrating starting structure independence of the average properties (e.g., potential energy, mean end-to-end distance). The end-to-end distance was defined as the distance between the terminal carbons. MC/SD simulation populations were determined by quenching the output structures to 0 K by exhaustive minimization and tabulating the number of times a given conformer appeared. Conformers were optimized to energy gradients less than 0.001 kcal/Å mol using the truncated Newton conjugate method.17 Force Fields. The all-atom Amber* and OPLS* force fields were used in all molecular mechanics calculations and simulations.13-15 Torsional parameters of the two force fields were modified to bring the stationary points (barriers heights and well depths) of three major conformers (TTT, TGT, TTG) in line with recent, high level, ab initio results.6,7 The modified Vn parameters are shown in Table 1.18 The rotational profile of interest was mapped by driving the dihedral angle between (180° in 5° increments, with torsional restraints applied to the other dihedrals to keep them trans. The modified force fields are referred to as Amber** and OPLS**, to distinguish them from the original MacroModel implementations, Amber* and OPLS*. Results and Discussion Gas Phase. As a prelude to condensed phase simulations, gas-phase molecular mechanics studies of DME were performed to assess the general quality of the Amber* and OPLS* force field parameters. In contrast to the high-level ab initio results, neither force field predicted the all-trans conformer as being the most stable; the TGG′ and TGT conformers were predicted by Amber* and OPLS* respectively. As shown in Table 2, conformer relative energies differed significantly from the theoretical predictions.6,7 Examination of the C-C and C-O rotational profiles revealed additional differences between the molecular mechanics and ab initio results. As is evident in Figure 1, molecular mechanics predicted a C-C skew barrier (saddle point between gauche and trans) that was too high while the C-C cis barrier (TCT) and both C-O barriers were underestimated. On the basis of a computed Boltzmann distribution at 300 K, dipole moments of 1.91 and 1.69 D were
TTT TGT TGG′ TTG TGG GGG GGG′ GG′G GTG′ GTG TTT TGT TTT TTG TCT
0.00 0.51 0.53 1.65 2.24 1.97 2.30 3.34 3.47 2.40 9.51
0.00 0.15 0.23 1.43 1.51 1.64 1.86 2.41 3.08 3.13
0.00 0.19 -0.19 0.82 0.90 0.60 0.73 0.38 1.33 1.70
0.00 0.48 0.22 1.40 2.25 3.61 1.86 2.55 2.51 2.74
0.00 -0.01 0.03 0.83 0.88 1.05 1.01 0.46 1.45 1.70
0.00 0.30 0.24 1.27 1.99 3.44 1.80 2.51 2.42 2.39
2.31 2.04 8.90
3.89 1.33 5.65
2.41 2.32 9.50
2.52 1.22 3.97
2.26 2.25 9.36
a
Taken from ref 7. b Data from ref 6. c Original (unmodified) force fields.
calculated for Amber* and OPLS*, respectively (values of 1.87 and 1.73 D were calculated from the results of MC/SD simulations using Amber* and OPLS*, respectively). These values are on the high end of reported experimental19 and theoretical values6 and can be attributed to the low all-trans population which is a result of the overestimation of the TTT energy by the force fields. (The dipole moment is very sensitive to the population of the TTT conformer which has zero dipole moment.) In addition, both force fields give an overall energy spacing (the difference between the most stable and the least stable conformer) that is significantly less than the ab initio value, thus overestimating the stability of higher energy conformers. Since the Amber* and OPLS* parameters for DME did not give results consistent with previous work, these parameters were modified. Tsuzuki et al.7 have calculated the energies of nine DME conformers (the GG′G conformer was not found) at the MP3/ 6-311+G*//HF/6-311+G* level, while Jaffe and co-workers6 have calculated conformer energies and barrier heights at the MP2/D95+(2df,p)//HF/D95** level. Using these ab initio calculations as guides, the C-C and C-O rotational barrier were adjusted. The V1, V2, and V3 cosine terms were adjusted manually to give adequate representations of the barrier heights and energies of the TGT and TTG conformers relative to that of the all-trans conformer. No attempt was made to adjust the relative energy of the TGG′ conformer and higher energy conformers were not considered. A comparison of ab initio and molecular mechanics conformer energies and geometries is given in Tables 2 and 3. Both the energies and geometries are satisfactorily represented by the modified force fields. The TGG′ energy predicted by the modified force fields is noteworthy, considering that no attempts were made to directly optimize this conformer. Although the order of relative energies differs somewhat for the six higher energy conformers, for five of these conformers, the absolute differences between the ab initio results and the molecular mechanics calculations are small. However, both force fields give a GGG conformer energy that is significantly higher (>1.0 kcal/mol) than the theoretical predictions. Examination of the energy components shows that an unfavorable van der Waals interaction (the GGG conformer has the highest van der Waals energy) and a relatively high electrostatic energy are responsible for its high energy in the molecular mechanics scheme. Smith et al.6 suggest that this conformer has a unique combination of oxygen lone pairmethyl hydrogen interaction and lone pair-lone pair interaction and that the energy discrepancy highlights the shortcomings of the force-field representation. It is unlikely that further torsional optimization will improve the energy of this conformer without adversely affecting the others. Even given the limitations of a
8226 J. Phys. Chem., Vol. 100, No. 20, 1996
Williams and Hall
Figure 1. Rotational profile of the O-C-C-O dihedral angle. Points shown are discrete energies calculated by driving the dihedral angle between (180° in 5° increments. Curve defined by these discrete values was generated using a cubic spline function. Torsional restraints applied to other dihedrals to keep them trans.
Figure 2. Rotational profile of the C-O-C-C dihedral angle. Points shown are discrete energies calculated by driving the dihedral angle between (180° in 5° increments. Curve defined by these discrete values was generated using a cubic spline function. Torsional restraints applied to other dihedrals to keep them trans.
diagonal force field with no explicit polarization treatment, improved charge and nonbonded parameters (e.g., deriving charges by restrained electrostatic potential fitting20 and optimizing van der Waals parameters to reproduce DME bulk properties) may result in a better representation of DME conformer energies. However, the molecular mechanics description of the higher energy conformers is satisfactory as they make little contribution to average thermodynamic properties of DME at room temperature. The performance of Amber** and OPLS** as measured by gas-phase MC/SD simulation results shows significant improvement over that of the unmodified force fields. Populations of the four most significant conformers (TTT, TGT, TGG′, and TTG) are more consistent with the ab initio and electron
diffraction results (Table 4). The percentage MC/SD simulation structures having a gauche C-C conformation is approximately 63.1% (Amber**) and 64.9% (OPLS**) compared with reported values of 58.1% (Bressanini et al., numerical integration of Boltzmann distribution for an isolated molecule),21 68.8% (Tsuzuki et al., ab initio calculations),7 70.0% (Smith et al., stochastic dynamics simulation),10 and 79.0% (electron diffraction data,3 R.I.S. analysis of NMR data10). Similarly, the anti preference of the C-O bond is accurately reproduced by both force fields (percent anti (MC/SD): Amber** ) 72.3, OPLS** ) 73.8). A dipole moment of 1.61 D was calculated for the Amber** simulation and 1.49 D for OPLS** in good agreement with both theoretical and experimental dipole measurements for DME.6,19 In principle, a much more extensive parametrization
Conformations of 1,2-Dimethoxyethane
J. Phys. Chem., Vol. 100, No. 20, 1996 8227
Figure 3. Computed population distributions for the O-C-C-O dihedral angle (MC/SD simulation). Curve defined by these discrete values was generated using a cubic spline function.
Figure 4. Computed population distributions for the C-O-C-C dihedral angle (MC/SD simulation). Curve defined by these discrete values was generated using a cubic spline function.
of bond, angle, and torsional potentials could be undertaken. This was not attempted however, since the performance of both force fields in condensed-phase simulations is excellent. Condensed Phase. Inclusion of the GB/SA solvation model has dramatic effects on conformer populations predicted by molecular mechanics and MC/SD. In water, the gauche C-C state is stabilized by approximately 0.6-0.7 kcal/mol relative to the gas phase (percent gauche (MC/SD): Amber** ) 82.8 , OPLS** ) 85.3), consistent with the trends seen in previous experimental and theoretical work.1,2,21,22 The rotational profiles of the C-C and C-O bonds, shown in Figure 1, indicate that solvation lowers both the barrier heights and the gauche conformer energies relative to that of the trans. The effect of the polar medium on the C-O bond, to favor the anti conformation slightly, is also consistent with the interpretation
of the NMR experiments4 and with other computational studies.9,21,22 A more careful examination of the data reveals that the TGT conformer is stabilized relative to the TTT and TGG′ conformers in CHCl3 and H2O, accounting for more than 30 and 50% of the respective populations. That the GB/SA model predicts a differential stabilization for the TGT conformer of approximately 1.1 and 0.9 kcal/mol relative to the TTT and TGG′ conformers, respectively, in aqueous solution, is particularly interesting as previous studies have shown that continuum models underestimate the solvation contribution to the gauchetrans equilibrium and may incorrectly predict a dominant TGG′ solution conformation.5,9,23 An initially attractive interpretation of the data is that the conformers with higher dipole moments are preferentially stabilized in more polar media. Consequently, polar conformers
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Williams and Hall
TABLE 3: Torsional Geometriesa of DME Conformers from ab Initiob Calculations and Molecular Mechanics Studies Using the Amber**c and OPLS**c Force Fields ab initio
Amber**
OPLS**
conformer
COCC
OCCO
CCOC
COCC
OCCO
CCOC
COCC
OCCO
CCOC
TTT TGT TGG′ TTG TGG GGG GGG′ GG′G GTG′ GTG
180.0 -174.7 -177.4 -178.8 -178.4 63.1 84.7
180.0 73.4 71.2 179.3 66.0 48.0 73.4
180.0 -174.7 -90.8 89.1 79.9 63.1 -80.7
89.2 90.5
180.0 177.9
-89.2 90.5
180.0 178.0 179.9 178.5 180.0 78.4 83.8 104.7 82.2 78.1
180.0 -78.6 -85.0 -175.2 74.9 64.7 84.2 -74.5 180.0 167.1
180.0 178.0 74.9 -81.7 83.1 78.4 -73.1 104.8 -82.3 78.2
180.0 177.8 179.2 178.4 179.7 83.2 85.4 108.3 84.6 78.8
180.0 -78.7 -87.8 -172.8 -74.9 66.6 86.4 -78.1 180.0 163.6
180.0 177.8 76.9 -82.5 -85.8 83.2 -76.2 108.3 -84.6 78.8
a
Dihedral angle measured in degrees, defined by the four atoms. b Ab initio data from ref 7. c Modified force fields.
TABLE 4: Populations of Selected DME Conformersa conformer
Amber*
Amber**
OPLS*
OPLS**
S.D.b
ab initioc
ab initiod
E.D.e
TTT TGT TGG′ + TGG TGG′ TTG other µ
0.11 0.16 0.51 0.43 0.10 0.12 1.87
0.27 0.20 0.41 0.40 0.09 0.03 1.61
0.14 0.27 0.42 0.34 0.09 0.08 1.73
0.25 0.25 0.38 0.36 0.09 0.03 1.49
0.21 0.28 0.38 0.34 0.09 0.04
0.16 0.27 0.47 0.43 0.05 0.05 1.58
0.25 0.20 0.47 0.45 0.06 0.02
0.13 0.23 0.53 0.03 0.08
a Comparison of major conformers populated at room temperature from MC/SD simulations at 300 K using original and modified force fields. Simulation without distant dependent dielectric ref 22. c Ab initio populations at 273.15 K from ref 6. d Ab initio populations at 273.15 K from ref 7. e Electron diffraction data at 273.15 K from ref 3. b
such as TGT and TGG are stabilized in CHCl3 and H2O while TTT and GTG′ (conformers having zero dipole moments) are destabilized. However, this analysis is only valid if dipolar interactions dominate and cannot explain the increased stabilization of the TGT conformer relative to the TGG′ conformer. Although a rigorous discussion of this observation is not within the range of this work, an analysis of the solvation energy terms indicates that the two conformers differ primarily in the magnitude of the generalized Born solvation component. A small but consistent increase in the dipole moment of the TGT conformer with increasing dielectric strength (H2O . CHCl3 . vacuum) is observed. Similar “polarizability” is observed for the TGG, TTG, and GGG′ conformers but not for the TGG′ conformer. The overall dipole moment of DME (rootmean-square value) is also observed to increase with increasing solvent polarity, consistent with other simulations21 and with the interpretation of experimental results.19 The Amber** and OPLS** force fields give very similar results in either CHCl3 and H2O (shown in Table 5). Although, the absence of the GG′G conformer in one of the OPLS** simulations (300 K simulation in water) parallels reports by Andersson and Karlstro¨m5 and Tsuzuki and co-workers,7 who were not able to optimize this conformer in gas-phase ab initio studies, it is probably an artifact of the relatively coarse sampling employed (only 5000 snapshots were saved over the course of the simulation). Both Amber** and OPLS** results suggest that this conformer is destabilized with increasing dielectric strength of the medium. Simulations performed at 315 K and at room temperature show little difference in conformer populations. However, the results from simulations at significantly higher temperatures may not be accurate, as the force fields have not been parametrized to reproduce the energies of higher energy conformers. Conclusion In this work, we have modified the DME C-C and C-O torsional potentials of the Amber* and OPLS* force fields to
TABLE 5: Condensed-Phase Conformer Populationsa,b Amber** conformer
CHCl3
OPLS** H2O
CHCl3
H2O
TTT TGT TGG′ TTG TGG GGG GGG′ GG′G GTG′ GTG
24.84 (24.44) 10.68 (11.32) 22.42 (21.98) 9.12 (9.00) 31.58 (31.26) 52.70 (50.92) 36.32 (35.46) 55.54 (54.44) 29.38 (28.84) 19.86 (19.86) 26.96 (25.88) 18.46 (18.54) 8.54 (9.24) 5.98 (5.78) 8.36 (9.64) 5.02 (5.70) 3.14 (2.98) 8.66 (9.52) 3.44 (4.06) 9.44 (9.20) 0.12 (0.10) 0.30 (0.26) 0.20 (0.16) 0.22 (0.32) 1.62 (1.94) 1.20 (1.44) 1.44 (1.90) 1.62 (1.88) 0.02 (0.04) 0.04 (0.08) 0.02 (0.04) (0.02) 0.42 (0.54) 0.20 (0.26) 0.34 (0.44) 0.22 (0.44) 0.34 (0.62) 0.38 (0.56) 0.48 (0.44) 0.36 (0.46)
C-Cc C-Od µe
65.86 (65.16) 82.76 (82.08) 68.38 (67.50) 85.28 (84.40) 76.95 (76.23) 80.63 (79.82) 78.13 (77.23) 81.12 (80.16) 1.68 (1.68) 1.91 (1.93) 1.58 (1.60) 1.83 (1.82)
a Populations from MC/SD simulations at 300 K. b Values in parentheses are from simulations at 315 K. c Percentage of gauche C-C dihedrals. d Percentage of trans C-O dihedrals. e Root mean square value.
reproduce high level ab initio calculations of relative conformer energies and barrier heights. These modified force fields (Amber** and OPLS**) show significant improvement over the original implementations in their ability to reproduce gasphase energies, populations, and dipole moments from molecular mechanics calculations and mixed Monte Carlo/stochastic dynamics simulations. The TGG′ conformation is adequately represented without the need for special parametrization or the addition of ad hoc energy terms. However, both force fields predict an energy for the GGG conformer that is much higher than the theoretical prediction. Condensed-phase molecular mechanics calculations and MC/ SD simulations using the modified force fields and the GB/SA solvation model successfully predict the differential stabilization of the C-C gauche conformers, with a net free energy stabilization of 0.6-0.7 kcal/mol, and also reproduce the high fraction of C-O anti conformers. The model correctly predicts the differential stabilization of the TGT conformer with respect
Conformations of 1,2-Dimethoxyethane to the TTT and TGG′ conformers. A 1 kcal/mol solvation energy stabilization of the TGT conformer relative to the alltrans is predicted by MC/SD simulations, comparable to explicit solvent simulations9 and consistent with experimental and theoretical studies. In conclusion, the Amber** and OPLS** force fields and GB/SA continuum model accurately reproduce the conformational properties of solvated DME and can be successfully used in molecular mechanics studies at a fraction of the computational expense of an explicit solvation model. Acknowledgment. The authors thank Dr. David Chalmers, Dr. Wendy Cornell, Professor Peter Kollman, Professor Garland Marshall, Dr. Quentin McDonald, and Dr. Hanoch Senderowitz for their helpful comments. We also wish to thank the Center for Molecular Design (Washington University) for time on a SGI Challenge. This work was supported in part by the NIH (GM46318) to K.B.H. References and Notes (1) Viti, V.; Indovina, P. L.; Podo, F.; Radics, L. Mol. Phys. 1974, 27, 541. (2) Podo, F.; Ne´methy, G.; Indovina, P. L.; Radics, L.; Viti, V. Mol. Phys. 1974, 27, 521. (3) Astrup, E. E. Acta Chem. Scand. 1979, A33, 655. (4) Tasaki, K.; Abe, A. Polym. J. 1985, 17, 641. (5) Andersson, M.; Karlstro¨m, G. J. Phys. Chem. 1985, 89, 4957. (6) Jaffe, R. L.; Smith, G. D.; Yoon, D. Y. J. Phys. Chem. 1993, 97, 12745. (7) Tsuzuki, S.; Uchimaru, T.; Tanabe, K.; Hirano, T. J. Phys. Chem. 1993, 97, 1346.
J. Phys. Chem., Vol. 100, No. 20, 1996 8229 (8) Inomata, K.; Abe, A. J. Phys. Chem. 1992, 96, 7934. (9) Liu, H.; Mu¨ller-Plathe, F.; van Gunsteren, W. F. J. Chem. Phys. 1995, 22, 1722. (10) Smith, G. D.; Jaffe, R. L.; Yoon, D. Y. J. Phys. Chem. 1993, 97, 12752. (11) Guarnieri, F.; Still, W. C. J. Comput. Chem., 1994, 15, 1302. (12) Still, W. C.; Tempczyk, A.; Hawley, R. C.; Hendrickson, T. J. Am. Chem. Soc. 1990, 112, 6127. (13) Weiner, S. J.; Kollman, P. A.; Case, D. A.; Singh, U. C.; Ghio, C.; Alagona, G.; Profeta, S.; Weiner, P. J. Am. Chem. Soc. 1984, 106, 765. Weiner, S. J.; Kollman, P. A.; Nguyen, D. T.; Case, D. A. J. Comput. Chem. 1986, 7, 230. (14) Jorgensen, W. L.; Tirado-Rives, J. J. Am. Chem. Soc. 1988, 110, 1657. (15) Amber* and OPLS* are MacroModel implementations of the respective force fields. Amber* uses the more recent 6,12 Lennard Jones treatment for hydrogen bonding (J. Comput. Chem. 1991, 12, 620). (16) Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.; Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J. Comput. Chem. 1990, 11, 440. (17) Ponder, J. W.; Richards, F. M. J. Comput. Chem. 1987, 8, 1016. (18) Original torsional parameters taken from Billeter, et al. J. Am. Chem. Soc. 1988, 110, 9620. (19) Viti, V.; Zampetti, P. Chem. Phys. 1973, 2, 233. (20) Cornell, W. D.; Cieplak, P.; Bayly, C. I., Kollman, P. A. J. Am. Chem. Soc. 1993, 115. (21) Bressanini, D.; Gamba, A.; Morosi, G. J. Phys. Chem. 1990, 94, 4299. (22) Smith, G. D.; Jaffe, R. L.; Yoon, D. Y. J. Am. Chem. Soc. 1995, 117, 530. (23) Nagy, P. I.; Bitar, J. E.; Smith, D. A. J. Comput. Chem. 1994, 15, 1228.
JP952581Y
