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 al l-atom Class II force field has been derived based on the recently rep orted CFF93 force field for hydrocarbons. It has been tested using bot h energy minimization and molecular dynamics (MD) simulations of the l ow-temperature neutron-diffraction structure of cholesteryl acetate cr ystals and the X-ray diffraction crystal structure of cholesterol. Thu s these studies test the techniques and limitations of high-accuracy c rystal simulations as well. Employing energy minimization, all cell ve ctors and volumes were reproduced to within 2.4% of experimental value s. For cholesteryl acetate, the root mean square (rms) deviations betw een the calculated and experimental bond lengths, angles, and torsions of nonhydrogen atoms are 0.013 Angstrom, 1.2 degrees, and 2.4 degrees , respectively. The corresponding maximum deviations are also very sma ll: 0.027 Angstrom for bond length, 3.2 degrees for angle, and 7.6 deg rees for torsion. For cholesterol, good agreement between the calculat ed and experimental structures was found only when the parison was lim ited to atoms with relatively small thermal factors (B-eq < 15 Angstro m(2)). It was found that for both systems, the MD averaged structures were in better agreement with the experimental ones than the energy mi nimized structures, since the rms deviations in atom positions are sma ller for the MD-averaged structures (0.064 Angstrom for cholesteryl ac etate and 0.152 Angstrom for cholesterol) than those for the minimized structures (0.178 Angstrom for cholesteryl acetate and 0.189 Angstrom for cholesterol). The force field was then applied to isolated molecu les focusing on the rigidity of the cholesteryl ring and cholesterol-c holesterol 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-ene rgy configurations and that it is more useful to describe each molecul e 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 th e equilibrium crystal structures. Limited results from a modified Clas s I (CVFF) force field are presented for comparison. (C) 1995 by John Wiley and Sons, Inc.