The ability of the Generalised AMBER Force Field (GAFF) to model the structure of
bisphosphonate ligands, C(R1)(R2)(PO3
2-)2, important compounds in the treatment of bone
cancer, by molecular mechanics methods is evaluated. The structures of fifty bisphosphonates
and nine bisphosphonate esters were predicted and compared with their crystal structures. Partial
charges were assigned from a RHF/6-31G* single point calculation at the geometry of the crystal
structure. Additional parameters required for GAFF were determined using the methods of the
force field’s developers. The structures were found to be well replicated with virtually all bond
lengths reproduced to within 0.015 Å (1.2s). Bond angles were reproduced to within 1.9o (0.8s).
The observed gauche or anti conformation of the molecules was reproduced, although in several
instances gauche conformations observed in the solid state energy-minimised into anti
conformations, and vice versa. The interaction of MDP (R1 = R2 = H), HEDP (R1 = OH, R2 =
CH3), APD (R1 = OH, R2 = (CH2)2NH3
+), alendronate (R1 = OH, R2 = (CH2)3NH3
+) and
neridronate (R1 = OH, R2 = (CH2)5NH3
+) with the (001), (010) and (100) faces of hydroxyapatite
was examined by energy-minimising twenty random orientations of each ligand 20 Å from the
mineral and then at about 8 Å from the surface whereupon the ligand relaxes onto the surface.
The difference in energy between the two systems is the interaction energy. In all cases
interaction with hydroxyapatite caused a decrease in energy. On the (001) face, both
phosphonate groups interact near a surface Ca2+ ion. The magnitude of the exothermic interaction
energy varies with molecular volume (MDP < HEDP < APD < alendronate) except for
neridronate, which interacts less effectively than alendronate because the long amino side chain
folds in on itself and does not align with the surface of the mineral. The bisphosphonates adopt
two conformations on the (010) face. In the first of these, found for MDP and 40% of the
alendronate structures, both phosphonates interact with the surface and the side chain points
away from the surface. In the second conformation, one phosphonate and the Ca side chain
interact with the surface. The interaction energy increases with the molecular volume of the
ligand, again with the exception of neridronate. Two conformations also occur on the (100)
face. In the first conformation, only one of the phosphonate groups points towards the surface
and the Ca side chain interacts with the surface; in the second conformation the Ca side chain
interacts strongly with the surface and both phosphonate groups point away from the surface
towards the solution. The first conformation is energetically more favourable. Its magnitude is virtually insensitive to the nature of the side chain and is similar to the magnitude of the
interaction energy on the other two faces. The magnitude of the second conformation increases
with the size of the Ca side chain
