Document Type



Doctor of Philosophy


Chemical Engineering

First Adviser

Mittal, Jeetain


Complex molecular networks of living organisms primarily involve proteins, bio-macromolecules which involve in every biochemical process of a living organism. As traditionally known, each protein carries out a unique function associated with the unique structure of each protein, which indeed is encoded in the amino acid sequence. Proteins acquire their unique “nativeâ€? structure following one of the most fundamental biological self-organization process. The progress accomplished in understanding of this physical process, called protein folding, significantly evolved our current understanding of how living organisms function.More recently, a more complete picture of the proteome from many organisms revealed that many proteins or regions in the proteins cannot form a stable structure, which are predicted to form more than one third of eukaryotic proteins. These proteins, referred as intrinsically disordered proteins, rather exist in a relatively huge conformational diversity as the ensembles of rapidly interconverting conformers. However, on the contrary to the traditional view, this group of proteins still perform many vital functions in the cell. In fact, their functionality possibly benefits from their being ability of adopting multiple conformers under similar conditions. While this versatile group of proteins modifies our understanding of the functioning properties of living organisms, many aspects are still remained much less well-understood, partly to blame the difficulty to work with them experimentally. In this regard, molecular simulations with accurate atomistic models provide a particular advantage not only resolving the heterogeneity in the conformational ensemble of these proteins but also providing the atomic level resolution of each conformer.This dissertation mainly aims at broadening our understanding of IDPs and unfolded proteins with the use of atomistic simulations. Many different coherent aspects of unfolded and disordered proteins are studied during the course of this dissertation, including butnot limited to sequence and temperature dependent responses of IDPs, post-translational modifications and disease-related characteristics of some IDPs. Each of these aspects studied in this dissertation also addresses where the atomistic simulations are relatively lacking and how the models and simulation techniques can possibly be improved.