Publication Date

5-2025

Date of Final Oral Examination (Defense)

3-7-2025

Type of Culminating Activity

Dissertation

Degree Title

Doctor of Philosophy in Biomolecular Sciences

Department

Biological Sciences

Supervisory Committee Chair

Julia Oxford, Ph.D.

Supervisory Committee Member

Allan Albig, Ph.D.

Supervisory Committee Member

Daniel Fologea, Ph.D.

Supervisory Committee Member

Lisa Warner, Ph.D.

Supervisory Committee Member

Richard Beard, Ph.D.

Abstract

Collagen α1(XI) is a minor fibrillar collagen involved in the critical regulation of collagen fibrils, such as nucleation, assembly, and regulation of fibril diameter. The amino-terminal domain consists of an amino-propeptide (Npp) domain and a variable region, which is the result of alternative splicing from exon 6A, 6B, 7, and 9. The spliced variants involving Npp, with the combinations of exon 6A, 6B, 7, and 9 gives rise to different isoforms with very distinctive chemical nature. The Npp of collagen α1(XI) chain is retained on the surface of the collagen fibril for an extended period of time and may play a key role in the interaction with extracellular matrix (ECM) glycosaminoglycans and other proteins during the fibrillogenesis process. However, how these chemically distinctive proteins may module collagen fibril formation is yet to be fully understood. To understand more about the structure of the Npp domain we used modeling tools such as AlphaFold 2 and Modeller for a comparative structural analysis with the already known structural features from the wet lab of this domain. Moreover, we also carried out molecular dynamics simulation (MD simulation) of the Npp domain with the structures obtained from AlphaFold 2 and Modeller for a comparative analysis. In order to understand the modulatory impact of these isoforms we measured self-assembly kinetics of collagen type I in the presence of different isoforms (A, B, and 0) and then calculated the thermodynamic parameters from the rate constants. Moreover, we modelled isoforms A, B, and 0 with AlphaFold 2. Later with these structures we carried out molecular dynamics simulations, protein-protein docking studies, and molecular mechanics Poisson-Boltzmann surface area with collagen type I to understand the molecular mechanisms behind this modulation of collagen type I self-assembly. In addition, we propose a possible mechanism of isoform B in the nucleation of hydroxyapatite with collagen type I from molecular dynamics simulation studies.

Comments

https://orcid.org/0000-0002-1331-9665

DOI

10.18122/td.2364.boisestate

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