Date of Award

Spring 2020

Document Type


Degree Name

Doctor of Philosophy (PhD)


Chemistry and Biochemistry



Committee Director

Lesley Greene

Committee Member

Jing He

Committee Member

Chris Osgood

Committee Member

Jennifer Poutsma


Predicting three-dimensional structures of proteins from sequence information alone, remains one of the most profoundly challenging and intensely studied problems in basic science. It has uniquely garnered the interdisciplinary efforts of biologists, biochemists, computer scientists, mathematicians and physicists. The advancement of computational methods to study fundamental features of proteins also enables insights that are either difficult to explore experimentally or complimentary to further interpret experimental data. In the present research and through the combined development and application of molecular dynamics and network science approaches we aimed to elucidate the role of geographically important amino acids and evolutionarily conserved long-range interactions which are proposed to be key to protein stability and topology. Using a model system of nine proteins that share a Greek-key topology, the proteins were unfolded under high temperature with molecular dynamics simulations. The unfolded trajectories were analyzed by calculating root-mean-square-deviation, contact distances, root-mean-square-fluctuation and fraction of remaining contacts. The results indicated that the conserved long-range interactions are significantly more persistent over time than the non-conserved long-range interactions thus dominant contributors to topological stability. The behavior of the conserved long-range interactions in the folding of our model proteins was also tested using simulated annealing and the formation of giant network clusters. The results demonstrated that the conserved interactions play a dominant role in folding by governing the native topology and facilitating rapid formation of the native network. In a third study, the role of the residues with high betweeness centrality scores in maintaining the protein network and in governing the Greek-key topology were examined by fragmentation and diameter tests. Here we found a subset of selected residues in similar geographical positions in all model proteins, which demonstrates the role of these specific residues and regions in governing the Greek-key topology from a network perspective. In conclusion, we can say that the determination of protein topology in terms of a network structure will facilitate predicting the folding and stability of proteins.





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