Bioinformatic analysis on the determinants of protein aggregation and conformational conversion
- Autores: Juan Valentín Iglesias Mas
- Directores de la Tesis: Salvador Ventura Zamora (dir. tes.)
- Lectura: En la Universitat Autònoma de Barcelona ( España ) en 2021
- Idioma: inglés
- Número de páginas: 193
- Títulos paralelos:
- Anàlisi bioinformàtica dels determinants de l'agregació proteica i la conversió conformacional
- Tribunal Calificador de la Tesis: Josep Vendrell Roca (presid.), Javier Sancho Sanz (secret.), Benjamin Lang (voc.)
- Programa de doctorado: Programa de Doctorado en Bioquímica, Biología Molecular y Biomedicina por la Universidad Autónoma de Barcelona
- Materias:
- Enlaces
- Tesis en acceso abierto en: TDX
- Resumen
- English
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.
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.
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.
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.
- English
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. 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. 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. 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.
- català
L’agregació de proteïnes ha passat de ser gairebé una curiositat biofísica sense major interès a un dels camps més actius de la recerca, especialment des que es va esbrinar que podia ser la causa de diverses malalties en humans. L’agregació en proteïnes ve determinada en un primer terme per la seva seqüència aminoacídica, que és qui delimita les possibles interaccions entre els seus aminoàcids. Diferents factors modulen aquesta propensió intrínseca a agregar. Sovint les proteïnes assoleixen un plegament natiu que és energèticament més estable i que usualment amaga regions propenses a agregar, i d’aquesta forma es prevé una oligomerització no funcional. No totes les proteïnes requereixen un plegament amb una estructura tridimensional definida; les proteïnes intrínsecament desordenades són un grup de polipèptids que manquen una arquitectura espacial definida, amb lo qual tenen una significativament major exposició al solvent; fet que incrementa el seu risc de formar contactes aberrants. Un cas especial de proteïnes desordenades o amb regions desestructurades són els prions i les proteïnes del tipus prió. Aquestes proteïnes es caracteritzen per tenir regions amb una baixa complexitat amb regions amb propensió críptica a agregar, que són capaces d’automodelar una conformació aberrant que s’acobla en forma d’agregats. La bioinformàtica ha assistit en l’estudi d’aquests diferents grups de proteïnes i dels diferents nivells estructurals que adopten, dotant-nos d’un seguit d’eines en forma d’algoritmes per modelar els seus comportaments en processos fisiopatològics. Aquests models computacionals van ser dissenyats fent servir el coneixement del qual es disposava en el seu moment. Però el ràpid increment en l’enteniment dels fenòmens que dirigeixen els processos com l’agregació proteica fan imperatiu una contínua revisió i millora en el desenvolupament d’aquests programes. La present tesi presenta una anàlisi bioinformàtica dels fenòmens darrere la compactació de proteïnes des de múltiples angles. Analitzant l’agregació de proteïnes des de l’estat natiu, proposem millores a la funcionalitat i la usabilitat d’un dels programes de predicció de referència. Tanmateix, s’analitzarà l’efecte del pH (com un primer intent d’integrar la situació on es troba la proteïna als càlculs) en els processos d’agregació i de plegament condicional en proteïnes intrínsecament desordenades. Els resultats obtinguts seran utilitzats per construir servidors web de caràcter obert, pensats com a solucions efectives a la vegada que econòmiques per a múltiples línies de recerca. El fenomen darrere la conversió priònica o de tipus prió serà analitzada per entendre els determinants que ho regulen i el rol funcional de les proteïnes que es sotmeten a aquesta transició; un aspecte sovint eclipsat per la seva associació amb malalties neurològiques. En general, el treball presentat en aquesta tesi intenta comprendre els determinants inter i intramoleculars que regeixen la compactació de les proteïnes, tant en condicions natives com canviants, i d’aquesta manera d’entendre el paper d’aquest procés tant en condicions fisiològiques com quan esdevé malaltia.
- English
