Bioinformatic analysis on the determinants of protein aggregation and conformational conversion

Abstract

Protein aggregation has moved from being an almost neglected biophysical curiosity to a central research field mostly due to aggregating proteins causing debilitating conditions in humans. The aggregation propensity of polypeptidic sequences is primarily dictated by their amino acid sequence, which delimits the possible interactions between amino acids. Different factors can modulate aggregation propensity. Achieving an energetic stable folded native state usually conceals aggregation prone-regions preventing aberrant self-oligomerization. Not all proteins fold into a defined three-dimensional structure; intrinsically disordered proteins are a group of polypeptides without a defined spatial architecture and therefore are significantly exposed to solvent; which increases the risk of forming aberrant contacts. A special case of disordered proteins or proteins with disordered regions are prions and prion-like proteins. These are characterized by low complexity regions with a cryptic aggregation propensity and able to self-template an aberrant conformation that self-assembles into aggregates._x000D_ _x000D_ Bioinformatics has assisted the study of these different kinds of proteins and protein structural levels by providing a toolbox of algorithms to model their behaviour in physiology and disease. These computational models were designed using methodology approximations that exploited the available knowledge at that time. Our understanding of the phenomena that govern processes such as protein aggregation is growing rapidly; therefore, the underlying principles behind these programs should be continuously revisited._x000D_ _x000D_ The present thesis provides a bioinformatics analysis of the phenomena behind protein compaction from multiple angles. By analysing protein aggregation in the native state, we propose improvements to both functionality and usability of a state-of-the-art globular prediction method. At the same time, the effect of pH (as a first approach integrating protein environment on calculations) on intrinsically disordered proteins aggregation and conditional folding was analysed. The obtained results will be used to build publicly accessible web servers as cost-effective tools for multiple research lines. The phenomenon behind prion and prion-like conversion will be studied to gain insight into the determinants that regulate this conversion and the functional role of proteins that undergo this transition; an aspect often overshadowed by their association with neurological diseases._x000D_ _x000D_ Overall, the work presented in this thesis attempts to understand fundamental inter- and intra-molecular determinants governing protein compaction in near-native and in changing environmental conditions, as a proxy to understand the role of this process in physiology and disease.

Date of Award	25 Mar 2021
Original language	English
Supervisor	Salvador Ventura Zamora (Tutor)