Neutron Diffraction and MD Studies of the Studies of the Structure of Aqueous Sol

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This proposed project will be the continuation of an on-going study of the structure of aqueous solutions of complex biomolecular solutes using a combination of MD simulations and neutron diffraction with isotopic substitution (NDIS) experiments. Although neutron diffraction is the most useful experimental method for the study of liquid structure, the complexity of the total scattering from a biomolecular solution has rendered such experiments very difficult to interpret in terms of specific structural details. The NDIS method was developed to help simplify the interpretation of this scattering, but for large asymmetric solutes such as sugars, the scattering still cannot be interpreted in terms of specific details since each substituted hydrogen atom is in a different environment. The present project has overcome this problem by using sugar solutes specifically substituted at only a single position, allowing the NDIS experiment to probe the atomic structuring around just a single atom. These still complicated specific structure factors can then be compared directly to those calculated from MD simulations, as a means of determining the accuracy of the simulations, and if the representation is good, the wealth of information available from the simulations can be used to interpret the experimental data in detail. This method has in effect opened a new field of structural analysis of complex molecules in aqueous solution. The proposed extension will apply these newly-developed procedures to further studies of structuring in aqueous solutions of additional important biological molecules. A new, experimental concentration-dependent analysis will allow the intermolecular solvation structure to be extracted separately from the intramolecular structure. Additional intramolecular structuring studies will be used to analyze hydrogen-bonding in solutes and the conformations of solutes and how they are affected by solvation. In addition to a systematic analysis of the biologically-important simple monosaccharides and their analogs, the technique will be extended to studies of amino acids, nucleotides, and other small biological solutes. This work is important for public health because of the importance of aqueous solvation in all biological systems, and in determining the functioning of biomolecules. Such basic information is essential in designing drug molecules and biological ligands and in understanding both disease mechanisms and the functioning of normal biological systems.