New computational methods to study the relationship between protein structure and function
Date
2022-08
Authors
Kumar, Ambuj
Major Professor
Advisor
Jernigan, Robert L
Dorman, Karin S
Song, Guang
Gupta, Mohan
Wu, Zhijun
Committee Member
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Abstract
Protein function prediction is one of the major challenges in molecular biology. Due to the generally higher protein structure conservation compared to sequence conservation, the study of protein structure-function relationship is one of the primary areas of research in structural biology. Some protein functions such as substrate binding, allostery, and protein-protein interaction can be investigated using protein fold similarities and dynamics. Protein secondary and tertiary structure arrangements, assemblages, and conformational transitions can contribute significant to protein function prediction. Molecular dynamics simulation, normal mode analysis and elastic network models have been commonly implemented to study the relationships among protein structure, dynamics, and function. The relationship between protein collective motions and allostery remains incomplete. The present work introduces computational methods to predict protein functional regions using protein structure and dynamics of the collective motions obtained from elastic network model (ENM).
The first method (PACKMAN) presented in this work enables the prediction of hinge residues within proteins by computing the packing density of all residues within proteins. The second method, Dynamic Community Identifier (DCI), uses dynamics to find groups of residues showing cohesive motion, which in turn assists in detecting functional domain and the corresponding allostery. In addition, this can be used to infer the community motions required to open cryptic pockets. The third method, Allostery Pocket Predictor (APOP), predicts allosteric ligand binding pockets within proteins, which can be utilized for drug design. The fourth method is a tool to investigate the relationship between entropy and enthalpy for ligand binding, which enables the impact of ligand binding. These methods collectively enable the study of many protein functions based on protein structure and dynamics.
PACKMAN (https://packman.bb.iastate.edu/), DCI (https://dci.bb.iastate.edu/), and APOP (https://apop.bb.iastate.edu/) are all easily accessible through user friendly web interfaces.
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dissertation