Full metadata
Title
Solvation Thermodynamics and Free Energy Surfaces of Intrinsically Disordered Proteins (IDPs) in Aqueous Solutions
Description
Contrary to the traditional structure-function paradigm for proteins, intrinsically disorderedproteins (IDPs) and regions (IDRs) are highly disordered sequences that lack a fixed
crystal structure yet perform various biological activities such as cell signaling, regulation,
and recognition. The interactions of these disordered regions with water molecules are essential
in the conformational distribution. Hence, exploring their solvation thermodynamics
is crucial for understanding their functions, which are challenging to study experimentally.
In this thesis, classical Molecular Dynamics (MD), 3D-Two Phase Thermodynamics (3D-
2PT), and umbrella sampling have been employed to gain insights into the behaviors of
intrinsically disordered proteins (IDPs) and water.
In the first project, local and total solvation thermodynamics around the K-18 domain
of the intrinsically disordered protein Tau were compared, and simulated with four pairs
of modified and standard force fields. In empirical force fields, an imbalance between
intramolecular protein interactions and protein-water interactions often leads to collapsed
IDP structures in simulations. To counter this, various methods have been devised to refine
protein-water interaction models. This research applied both standard and adapted force
fields in simulations, scrutinizing the effects of each adjustment on solvation free energy.
In the second project, the MD-based 3D-2PT analysis was utilized to examine variations
in local entropy and number density of bulk water in response to an electric field, focusing
on the vicinity of reference water molecules.
In the third project, various peptide sequences were examined to quantify the free energy
involved when specific sequences, known as alpha-MoRFs (alpha-Molecular Recognition
Features), transition from intrinsically disordered states to structured secondary motifs
like the alpha-helix. The low folding free energy penalty of these sequences can be exploited
to design peptide-based or small-molecule drugs. Upon binding to alpha-MoRFs,
these drugs can stabilize the helix structure through a binding-induced folding mechanism.
Alpha-MoRFs were juxtaposed with entirely disordered sequences from known proteins,
with findings benchmarked against leading structure prediction models. Additionally, the
binding free energies of various alpha-MoRFs in their folded conformation were assessed
to discern if experimental binding free energies reflect the separate contributions of folding
and binding, as obtained from umbrella sampling simulations.
Date Created
2024
Contributors
- Maiti, Sthitadhi (Author)
- Heyden, Matthias (Thesis advisor)
- Ozkan, S. Banu (Committee member)
- Sulc, Petr (Committee member)
- Arizona State University (Publisher)
Topical Subject
Resource Type
Extent
222 pages
Language
eng
Copyright Statement
In Copyright
Primary Member of
Peer-reviewed
No
Open Access
No
Handle
https://hdl.handle.net/2286/R.2.N.193412
Level of coding
minimal
Cataloging Standards
Note
Partial requirement for: Ph.D., Arizona State University, 2024
Field of study: Chemistry
System Created
- 2024-05-02 01:28:02
System Modified
- 2024-05-02 01:28:10
- 6 months 1 week ago
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