Understanding the Structure and Dynamics of Supramolecular Assemblies and Peptides in Solution

Abstract

Large complex supramolecular assemblies to small dipeptides all have significantly different dynamical and structural properties in solution. In the first part of the dissertation, a detailed theoretical investigation of the dynamics of a solution-phase supramolecular assembly is presented to provide new insights into its complex dynamical properties. A hydrogen-bonded hexameric supramolecular assembly is investigated using molecular dynamics simulations. Six resorcin[4]arene monomer units and eight water molecules form a hexameric assembly in water-saturated chloroform by encapsulating six chloroform molecules. It has promise as an effective catalytic vessel that can modify reaction pathways and selectivity through the encapsulations of reactants and catalyst in its ~1400 Å3 volume. In Chapter 2, the interactions between water and a hexameric resorcin[4]arene assembly formed in wet chloroform are examined by molecular dynamics simulations of the diffusion coefficients. It is found that the water diffusion coefficients provide a route to understanding the degree of water association with the assembly. The simulated diffusion coefficients are in excellent agreement with prior measurements, and the diffusion data are well described by a simple adsorption model. This analysis demonstrates that a significant number of waters are encapsulated within the assembly or hydrogen-bonded to its exterior, consistent with and elucidated by a direct examination of the water molecules in the simulations. In Chapter 3, molecular dynamics simulations are used to investigate the timescales of water encapsulation in this assembly in wet chloroform. It is shown that at low water content, there are three distinct populations of water molecules present. In contrast, an additional population, long water chains interacting with the assembly, appears at higher water content. The relative free energies of these different water positions are calculated, and time correlation functions are used to determine the timescales for inter-conversion between the populations. This analysis demonstrates that the water molecules are in rapid exchange on timescales of tens of ps to a few ns and suggests that water molecules might act as a critical component in the guest exchange mechanism. In Chapter 4, the dynamics of the water molecules in the hexameric assembly and surrounding solution in the absence and presence of different tetraalkylammonium salts is examined to interpret NMR experiments and elucidate the effect of different guests on the role of water molecules in the stability and dynamics of the hexameric capsule.Understanding the structure of proteins is key to unraveling their function in biological processes. Thus, significant attention has been paid to the calculation of conformational free energies. In the second part of this dissertation, a simple extension of fluctuation theory is demonstrated that permits the calculation of the temperature derivative of the conformational free energy, and hence the internal energy and entropy, from single temperature simulations. The method further enables the decomposition into the contribution of different interactions present in the system to the internal energy surface. The method is illustrated for the canonical test system of alanine dipeptide in an aqueous solution, for which the free energy is examined as a function of two dihedral angles. This system, like many, is most effectively treated using accelerated sampling methods, and we show how the present approach is compatible with an important class of these, those that introduce a bias potential, by implementing it within metadynamics.