This research is a general theoretical investigation of solvent effects on molecular and biomolecular conformational stability using molecular quantum mechanics, statistical thermodynamics and computer graphics, and is a unit of a continuing study of the role of conformation in chemical transmission in cholinergic neural processes. The project builds upon our recent papers on theoretical aspects of solvent effects and studies of the molecular structure of cholinergic molecules in free space and solution. A statistical thermodynamic analysis of solvent effects carried out in this laboratory displays the relations among the solvation models currently used and indicates the path to improved theoretical treatments of the problem. Working in terms of a reduced partition function for conformational variables of a dissolved molecule, the solute and first solvation shell imbedded in a polarizable dielectric continuum is treated in terms of statistical mechanics to produce a "supermolecule-continuum" model includes both inter-and intramolecular bulk dielectric effects and specific solute-solvent binding, with Monte Carlo configurational averaging in the first solvation shell. We propose herein to a) implement calculations for each of a progression of methods along the path to full quantum statistical mechanical supermolecule-continuum calculations for solvent effects on conformation stability, b) to systematically document the capabilities of each method in calculations on selected monatomic and small polyatomic prototype systems with all cholinergic functional groups represented, and c) apply what emerge as appropriate methods to theoretical studies of conformational problems of cholinergic moleculs in solution. The methods will be generally applicable to other molecular and biomolecular systems where the nature of solvent effects on conformation are of interest. BIBLIOGRAPHIC REFERENCES: A statistical Thermodynamic Supermolecule-Continuum Study of Ion Hydration I. Site Method. G.W. Schnuelle and D.L. Beveridge, J. Phys. Chem. 79, 2556 (1975). The Free Energy of a Change Distribution in Concentric Dielectric Continua, D.L. Beveridge and G.W. Schnuelle, J. Phys. Chem. 79, 2562 (1975).