Force field studies of cholesterol and cholesteryl acetate crystals and cholesterol–cholesterol intermolecular interactions

To model the physical properties of sterols and related species, an all-atom Class II force field has been derived based on the recently reported CFF93 force field for hydrocarbons. It has been tested using both energy minimization and molecular dynamics (MD) simulations of the low-temperature neutron-diffraction structure of cholesteryl acetate crystals and the X-ray diffraction crystal structure of cholesterol. Thus these studies test the techniques and limitations of high-accuracy crystal simulations as well. Employing energy minimization, all cell vectors and volumes were reproduced to within 2.4% of experimental values. For cholesteryl acetate, the root mean square (rms) deviations between the calculated and experimental bond lengths, angles, and torsions of nonhydrogen atoms are 0.013 Å, 1.2°, and 2.4°, respectively. The corresponding maximum deviations are also very small: 0.027 Å for bond length, 3.2° for angle, and 7.6° for torsion. For cholesterol, good agreement between the calculated and experimental structures was found only when the comparison was limited to atoms with relatively small thermal factors (B_eq < 15 Ų). It was found that for both systems, the MD averaged structures were in better agreement with the experimental ones than the energy minimized structures, since the rms deviations in atom positions are smaller for the MD-averaged structures (0.064 Å for cholesteryl acetate and 0.152 Å for cholesterol) than those for the minimized structures (0.178 Å for cholesteryl acetate and 0.189 Å for cholesterol). The force field was then applied to isolated molecules focusing on the rigidity of the cholesteryl ring and cholesterol–cholesterol interaction energies. It is concluded that the cholesteryl ring is fairly rigid since no major conformational change was observed during an MD simulation of a single cholesterol molecule in vacuo at 500 K, in agreement with condensed phase experiments. Calculations of cholesterol–cholesterol pairs suggest that there are only four low-energy configurations and that it is more useful to describe each molecule as having a plane (flat face) and two grooves rather than as having two (one flat and one rough) faces. This provides some insight into the equilibrium crystal structures. Limited results from a modified Class I (CVFF) force field are presented for comparison. © 1995 by John Wiley & Sons, Inc.