In the absence of force field topological fragments and RESP atom charge values for triazole derivatives in the Glycam 2004 force field, a new force field topology database (FFTPDB) compatible with the triazole derived glycoclusters and more generally with any glucose-α(1-4) based polymers was developed. Multiple molecules multiple conformations, and multiple molecular orientations were used in the charge derivation. Five molecules (β-D-glucose, α-D-glucose, α-methyl-D-glucoside, α-methyl-D-mannoside and 1-N-methyl-4-(2-hydroxyethyl)-1,2,3-triazole) were involved in the charge derivation (Scheme 1A).

For each of these molecules, two conformations were selected as reported in AMBER force fields. Omega dihedral angle conformations gauche, gauche and gauche, trans for the glucose and mannose derivatives were selected since these populations are the most commonly observed in solution. In the absence of experimental data for 1-N-methyl-1,2,3-triazole-4-ethan-2-ol the two lowest minima observed after geometry optimization were chosen. Optimized geometries presenting intra-molecular hydrogen bond were excluded from the charge derivation in order to avoid over-polarization effect. This approach is compatible with the use of implicit polarization in AMBER and GLYCAM force fields. Thus, for glucose and mannose derivatives geometry optimization was carried out in presence of dihedral angle constraints. The HO4'-O4'-C4'-H4' dihedral angle of the monosaccharides was constrained to a value of 180 deg. A second constraint for the HO2'-O2'-C2'-H2' dihedral angle of β-glucose and for the HO3'-O3'-C3'-H3' dihedral angle of α-methyl-mannoside was used, and set to values of 180 and 60 deg., respectively. Frequencies were calculated for all the molecules, and transition state structures were excluded from the charge derivation procedure. Geometry optimization, frequency calculation and molecular electrostatic potential (MEP) computation were carried out using the Gaussian 98 program in gas phase, while charge fitting was performed using the RESP program. The HF/6-31G** theory level was used in geometry optimization and frequency calculation. MEP computation was carried out using the HF/6-31G* theory level, and the CHELPG algorithm. The molecular orientation of the optimized geometries was controlled using the rigid-body reorientation algorithm implemented in the R.E.D. program. Four molecular orientations (based on the C1' C3' C5', C5' C3' C1', C2' C4' O5' and O5' C4' C2' atom names for glucose and mannose derivatives, and based on the OH C1 C2, C2 C1 OH, C2 C3 N4, N4 C3 C2 atom names for the triazole derivative) for each optimized geometry were generated before MEP computation, and involved in the charge fitting procedure to yield reproducible atom charge values. Charge fitting was performed using a single RESP stage, and a hyperbolic constraint value of 0.01. Inter-molecular charge constraints between the methyl group of α-methyl-glucoside, α-methyl-mannoside and 1-N-methyl-1,2,3-triazole-4-ethan-2-ol, and the anomeric, 4- or 6-hydroxyl group of α-methyl-glucoside, α-glucose and β-glucose or the hydroxyl group of 1-N-methyl-1,2,3-triazole-4-ethan-2-ol were used in charge fitting allowing the definition of the required molecular fragments. Intra-molecular charge constraint between the methyl and 4-hydroxyl groups of α-methyl-glucoside leads to the definition of glucose fragment suitable for the building of polymeric Glc-α-(1,4) based oligosacharides, or [Glc-α(1-4)]n glycoclusters (Schemes 1A and 1B). The charge value of each hydrogen bound to a carbon presenting a sp3 hybridization was set to a constrained value of zero in order to insure a compatibility between this work and the Glycam 2004 force field. The charge derivation procedure was automatically carried out using a version IV β of the R.E.D. program. A RRMS (relative root mean square value between the MEP values calculated by quantum mechanics, and those generated using the derived charge values) of 0.126 was obtained for the fit. Intra-molecular charge constraints, inter-molecular charge constraints, charge value equivalencing between the different molecular orientations and conformations, and the hyperbolic constraint of the restrained fit are accountable for an increase of 0.005, 0.003, 0.010, and 0.006 of the RRMS value, respectively. These values rigorously demonstrate the strength and the weakness of the approach followed.