Carbohydrate Research 344 (2009) 2217–2228 Contents lists available at ScienceDirect Carbohydrate Research journal homepage: www.elsevier.com/locate/carres Comparison of different force fields for the study of disaccharides Carlos A. Stortz a,*, Glenn P. Johnson b, Alfred D. French b, Gábor I. Csonka c a Departamento de Química Orgánica-CIHIDECAR, FCEyN-Universidad de Buenos Aires, Ciudad Universitaria, 1428 Buenos Aires, Argentina b Southern Regional Research Center, U.S. Department of Agriculture, 1100 Robert E. Lee Blvd., New Orleans, LA 70124, USA c Department of Inorganic and Analytical Chemistry, Budapest University of Technology, Szent Gellért tér 4, Budapest H-1521, Hungary article info abstract Article history: Eighteen empirical force fields and the semi-empirical quantum method PM3CARB-1 were compared for Received 26 May 2009 studying b-cellobiose, a-maltose, and a-galabiose [a-D-Galp-(1?4)-a-D-Galp]. For each disaccharide, the Received in revised form 13 August 2009 energies of 54 conformers with differing hydroxymethyl, hydroxyl, and glycosidic linkage orientations Accepted 18 August 2009 were minimized by the different methods, some at two dielectric constants. By comparing these results Available online 22 August 2009 and the available crystal structure data and/or higher level density functional theory results, it was con- cluded that the newer parameterizations for force fields (GROMOS, GLYCAM06, OPLS-2005 and CSFF) give Keywords: results that are reasonably similar to each other, whereas the older parameterizations for Amber, CHARMM Force field or OPLS were more divergent. However, MM3, an older force field, gave energy and geometry values com- Disaccharides Molecular mechanics parable to those of the newer parameterizations, but with less sensitivity to dielectric constant values. Cellobiose These systems worked better than MM2 variants, which were still acceptable. PM3CARB-1 also gave ade- Maltose quate results in terms of linkage and exocyclic torsion angles. GROMOS, GLYCAM06, and MM3 appear to Galabiose be the best choices, closely followed by MM4, CSFF, and OPLS-2005. With GLYCAM06 and to a lesser extent, CSFF, and OPLS-2005, a number of the conformers that were stable with MM3 changed to other forms. Ó 2009 Elsevier Ltd. All rights reserved. 1. Introduction optimization (flexible residues) was just becoming available, but some early versions did not specifically treat the exoanomeric ef- Knowledge of the three-dimensional structures of disaccharides fect. is essential for understanding biological and physical functions. The anomeric effect is thought to arise from a combination of Determinations of the conformational preferences and variability electrostatic effects and rearrangement of the electronic structure, of disaccharides are useful not only for the disaccharides them- giving stabilization to certain conformations and not others. Such selves, but can often also apply to oligo- and polysaccharides hav- problems are the domain of electronic structure theory (quantum ing the same primary structure.1 This understanding can be aided mechanics or QM), which also has the capacity to describe all other by reliable molecular modeling. In the beginning, computerized molecular properties, including hydrogen bonding. In principle, disaccharide modeling relied on very simple models that varied quantum mechanics could answer most of the questions being the torsion angles of the glycosidic linkage but not the geometries asked in MM studies. Apparent success with the Hartree–Fock of the monosaccharide residues. Back then, structures were rated (HF) methods and modestly sized basis sets relies too much on as either ‘allowed’ or ‘disallowed’ based on interatomic distances. cancellation of errors, limiting the possibility of improvement. Later, potential energies were calculated for the rigid residue mod- Density functional theory (DFT) can provide reasonable results els based on van der Waals forces, twisting about bonds, and some- for saccharides,4 but at present it is also expensive in terms of com- times, emulation of hydrogen bonding. The HSEA2 and PFOS3 puter time and memory for large-scale calculations. Correlated potential energy functions for carbohydrates employed torsional wavefunction theory (e.g., MP2 or CCSD(T)) is even more expen- potentials that explicitly accounted for the exoanomeric effect sive. Although QM methods continue to improve, there is still a but still used rigid residues. This was a problem because the results great body of work for which MM methods are more suitable. from such studies depended very much on the particular choice of atomic coordinates used in the rigid residues.3 General-purpose molecular mechanics (MM) software that provided full geometry In MM software, the exoanomeric effect is supported in two ways. The more important is the recognition that the O–C–O–C torsión angle should have different parameters than the C–O–C–C torsión angle. Force fields do not meet that requirement if they base torsional energies on X–C–O–X, where X is any atom. * Corresponding author. Tel./fax: +54 11 4576 3346. Additionally, there are significant bond length variations associated with the E-mail address: [email protected] (C.A. Stortz). anomeric effect, and this has also been parameterized for some force fields. 0008-6215/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.carres.2009.08.019 2218 C. A. Stortz et al. / Carbohydrate Research 344 (2009) 2217–2228 MM methods now often employ parameters that allow the MM QM/MM method.31 The hybrid method was especially useful for software to mimic the results from QM studies on fragments of modeling sucrose. The conformational space of the desialyated Le- disaccharides. This allows MM to account for many factors, includ- wis X trisaccharide and its analogues was probed with HF and ing the exoanomeric effect. MM2* levels of theory.32 Momany and co-workers studied differ- Disaccharide analysis by modeling is a large-scale problem even ent conformations of maltose and cellobiose using DFT.33,34 Even if there is no worry about changes in the form of the pyranosyl though very large amounts of computer time were required, later rings. Disaccharide shapes are analyzed either by generating a QM studies yielded full maps of disaccharides, considered greater Ramachandran-like conformational map (contour map of energy numbers of conformers, or even undertook larger oligosaccha- vs / and w), or just by finding the energies of isolated minima. In rides.35–39 either case, such studies might explain experimental results. While Despite the improved MM methods, the chosen force field still it is often considered that the glycosidic torsion angles / and w influences the results. In 1998, Pérez et al. analyzed several mono- (Fig. 1) are the main variables of shape, there will be numerous sta- saccharides and a single disaccharide with different force fields ble conformers (‘multiple minima’)5 with different energies result- that were available then,40 focusing more on comparing the force ing from different combinations of the orientations of the primary fields to each other rather than on comparisons with the experi- and secondary hydroxyl groups. Preference for the given values of mental values. Since then, only a few comparisons of MM methods / and w will often depend on a particular combination of exocyclic have been published41 in spite of the new parameterizations and group orientations. For example, cellobiose has, in addition to / and functional variants for carbohydrates.24–29 Comparison of HF, hy- w, 10 exocyclic bonds about which rotation can occur. If each is al- brid DFT and MM2* results showed the difficulties in predicting lowed three staggered orientations, there would be 310 = 59,049 energies for carbohydrates with MM methods,42 attributed to their possible structures (for each /,w point). Many would not be stable, densely packed, highly polar functional groups, and the depen- but unless all are evaluated, it could be that the lowest energy value dence of conformational energies on stereoelectronic effects. will not have been found. In modeling studies, a frequent task is to MM2* gave good qualitative results for the lowest energy rotamers compare the depths of different energy wells on a /,w surface. In of monosaccharides, in spite of showing an energetically com- such work it is necessary to give a reasonably complete treatment pressed conformational space with incorrectly ordered rotamers of the exocyclic group orientations for each well to get an answer in the higher energy region. Other comparisons with several force that fully represents the particular computational method. fields have been made for QM results for glucose.43 Comparisons Flexible residue analysis3,6–8 of disaccharides started around have also been made with higher saccharides.32 1979 and by the late 1980s the first fully relaxed energy maps of Herein, we compare the performance of 18 different force fields numerous disaccharides had been constructed.9–11 Except for the or variants, some of them at two different dielectric constants, early Melberg and Rasmussen calculations,6–8,12 most were carried working with a set of 54 conformers each of b-cellobiose, a-malt- 13 out with Allinger’s MM2, by carbohydrate-specific variants like ose, and a-galabiose [a-D-Galp-(1?4)-a-D-Galp](Fig. 1) with vary- 3 14 MM2CARB, or with CHARMM and the carbohydrate parameters ing hydroxymethyl and hydroxyl group orientations. Although of Ha et al.15 Subsequently, MM3, an all-atom force field with up- PM3 and other semiempirical molecular orbital methods have graded parameterization for anomeric effects on torsional energies been shown to fail with carbohydrates,44 a variant parameterized and bond lengths as well as hydrogen bonding,16 was released and for carbohydrates (PM3CARB-145) has been issued. The perfor- used for many disaccharide studies.17–20 Earlier in the 1980s, many mance comparison with this semiempirical method is also new force fields were developed, some of them especially intended included. for molecular dynamics (MD) in general (like GROMOS21).