Molecular Geometry

For the discussion, pick a topic of your choice that is related to this week’s reading material-Molecular Geometry. Molecular geometries of molecules often play an important role in determining the properties and/or function of that molecule, especially in biological molecules. Take for example, protein folding, which is part of the post-translational process proteins regularly undergo. In most cases, proteins are modified and properly folded, that is, they end up with the structure and function that genetics (DNA) indicated they would. In some cases, however, a mutation is introduced during abnormal transcription-translation (DNA-RNA- protein), two or more amino acids change their position within the protein molecule, new bonds (hydrogen, S-S, etc.) are formed or old bonds are disrupted causing change in protein conformation. One of such scenarios is familial Alzheimer’s disease resulting from mutated and misfolded protein, called presenilin (PS1). Mutations cause PS1 to adopt “closed” or compact conformation that is associated with increased production of toxic amyloid beta42 peptides (see schematics). Abeta42 impairs synaptic function causing memory problems. We have recently found that similar changes in PS1 occur during aging and are observed in sporadic AD cases, which means that there are some factors in our brains (not a mutation) that cause these pathogenic changes in PS1 protein geometry. My lab is currently looking for these factors as potential new therapeutic targets to stop or prevent AD pathogenesis. Here is another slide from our “Working hypothesis” series, showing a vicious circle with different stressors causing change in PS1 leading to increased Abeta42, which further triggers calcium dishomeostasis, inflammation, reactive oxygen species generation, etc. (Fig.1). Blue “clump” is an amyloid beta plaque (senile plaque) that deposits in the brain of AD patients but is also observed in ~25-30% of cognitively normal aging adults.  An example of a drug Diazepam (Valium) is given in your textbook at the beginning of Chapter 9. Elaborate and/or propose other examples of how changes in the molecular architecture of a compound affect its properties and/or effectiveness of binding to a specific cell receptor. The disease results from a mis-folded protein which is the consequence of the molecular geometries of the molecules that make up the protein structure.Feel free also to discuss some real life examples of when enthalpies are important to us.