Date of Award


Document Type


Degree Name

Doctor of Philosophy (PhD)



Committee Chair/Advisor

Dr Brian Dominy

Committee Member

Dr Steve Stuart

Committee Member

Dr Andrew Brown

Committee Member

Dr William Richardson


The focus of this research is to investigate the effects of allostery on the function/activity of an enzyme, human immunodeficiency virus type 1 (HIV-1) protease, using well-defined statistical analyses of the dynamic changes of the protein and variants with unique single point substitutions 1. The experimental data1 evaluated here only characterized HIV-1 protease with one of its potential target substrates. Probing the dynamic interactions of the residues of an enzyme and its variants can offer insight of the developmental importance for allosteric signaling and their connection to a protein’s function. The realignment of the secondary structure elements can modulate the mobility along with the frequency of residue contacts as well as which residues are making contact together2-5. We postulate that if there are more contacts occurring within a structure the mobility is being constrained and therefore gaining novel contacts can negatively influence the function of a protein.

The evolutionary importance of protein dynamics is probed by analyzing the residue positions possessing significant correlations and the relationship between experimental information1 (variant activities). We propose that the correlated dynamics of residues observed to have considerable correlations, if disrupted, can be used to infer the function of HIV-1 protease and its variants. Given the robustness of HIV-1 protease the identification of any significant constraint imposed on the dynamics from a potential allosteric site found to disrupt the catalytic activity of the variant is not plainly evident. We also develop machine learning (ML) algorithms to predict the protein function/activity change caused by a single point substitution by using the DCC of each residue pair. Recognition of any substantial association between the dynamics of specific residues and allosteric communication or mechanism requires detailed examination of the dynamics of HIV-1 protease and its variants.

We also explore the non-linear dependency between each pair of residues using Mutual Information (MI) and how it can influence the dynamics of HIV-1 protease and its variants. We suggest that if the residues of a protein receive more or less information than that of the WT it will adversely impact the function of the protein and can be used to support the classification of a variant structure. Furthermore, using the MI of residues obtained from the MD simulations for the HIV-1 protease structure, we build a ML model to predict a protein’s change in function caused by a single point substitution. Effectively the mobility, dynamics, and non-linear features tested in these studies are found to be useful towards the prediction of potentially drug resistant substitutions related to the catalytic efficiency of HIV-1 protease and the variants.



To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.