Inverse Monte Carlo simulation of biomolecular conformation and coarse-grained molecular modeling of chondroitin sulfate conformation, titration, and osmotic pressure

摘要

The first part of this thesis is concerned with the solution structure determination problem. Whereas many biomacromolecules, such as proteins, can be adequately characterized by a single conformation in solution, numerous other important molecules (e.g., nucleic acids, carbohydrates, and polypeptides) exhibit conformational isomerism and disorder. For these molecules, the term "structure" does not correspond to a single conformation but rather to an ensemble of conformations. Given a molecular model and experimental data, the goal of the structure determination problem is to solve for an ensemble of conformations that is consistent with the data. Traditional computational procedures such as simulated annealing, however, are not guaranteed to generate a unique ensemble. The computed ensemble is often simply dependent on the user-specific protocol employed to generate it. As an alternative, a numerical method for determining the conformational structure of macromolecules is developed and applied to idealized biomacromolecules in solution. The procedure generates unique, maximum entropy conformational ensembles that reproduce thermodynamic properties of the macromolecule (mean energy and heat capacity) in addition to the target experimental data. As an evaluation of its utility in structure determination, the method is applied to a homopolymer and a heteropolymer model of a three-helix bundle protein. It is demonstrated that the procedure performs successfully at various thermodynamic state points, including the ordered globule, disordered globule, and random coil states. In the second part of this thesis, a molecular model is developed and used to investigate the properties of anionic glycosaminoglycan (GAG) molecules. GAGs are critically important to the structure and biomechanical properties of articular cartilage, an avascular tissue that provides a low-friction, protective lining to the ends of contacting bones during join locomotion.