On the Approximation of Solvent Effects on the Conformation and Dynamics of Cyclosporin A by Stochastic Dynamics Simulation Techniques

Abstract

The molecular simulation technique of stochastic dynamics (SD) is tested by application to the immunosuppressive drug cyclosporin A (CPA). Two stochastic dynamics simulations are performed, one (SD_CCl4 ) with atomic friction coefficients proportional to the viscosity of the nonpolar solvent CCl₄, and one (SD_H2O) with atomic friction coefficients corresponding to an aqueous solution. The atomic friction coefficients are also taken proportional to an approximate expression for the atomic accessible surface area. The properties of both stochastic dynamics simulations are compared to those of two full molecular dynamics (MD) simulations of cyclosporin A, one in a box with 591 CCl₄ molecules, and one in a box with 632 H₂O molecules.

The properties of cyclosporin A as found in the molecular dynamics simulation in CCl₄ are well reproduced by the SD_CCl4 simulation. This indicates that the neglect of a mean force reresenting the average solvent effects on the solute is justified in the case of nonpolar solvents. For polar solvents, like water, this mean force may not be neglected. The SD_H2O simulation of cyclosporin A clearly fails to reproduce the amount of hydrogen bonding found in the molecular dynamics stimulation of cyclosporin A in water.

A comparison with a molecular dynamics simulation of cyclosporin A in vacuo shows that both the SD_CCl4 and the SD_H2O simulation come closer to the properties of the molecular dynamics simulations in CCl₄ and in H₂O than a molecular dynamics simulation in vacuo.

Key Words:

• Stochastic dynamics
• solvent effects
• cyclosporin A
• molecular simulation
• potential of mean force