Protein aggregation into amyloid fibrils is the archetype of aberrant biomolecular self-assembly processes, with more than 50 associated diseases that are mostly uncurable. Understanding aggregation mechanisms is thus of fundamental importance and goes in parallel with the structural characterization of the transient oligomers formed during the process. Oligomers have been proven elusive to high-resolution structural techniques, while the large sizes and long time scales, typical of aggregation processes, have limited the use of computational methods to date. To surmount these limitations, we here present multi-eGO, an atomistic, hybrid structure-based model which, leveraging the knowledge of monomers conformational dynamics and of fibril structures, efficiently captures the essential structural and kinetics aspects of protein aggregation. Multi-eGO molecular dynamics simulations can describe the aggregation kinetics of thousands of monomers. The concentration dependence of the simulated kinetics, as well as the structural features of the resulting fibrils, are in qualitative agreement with in vitro experiments carried out on an amyloidogenic peptide from Transthyretin, a protein responsible for one of the most common cardiac amyloidoses. Multi-eGO simulations allow the formation of primary nuclei in a sea of transient lower-order oligomers to be observed over time and at atomic resolution, following their growth and the subsequent secondary nucleation events, until the maturation of multiple fibrils is achieved. Multi-eGO, combined with the many experimental techniques deployed to study protein aggregation, can provide the structural basis needed to advance the design of molecules targeting amyloidogenic diseases.

Multi-eGO: An in silico lens to look into protein aggregation kinetics at atomic resolution / E. Scalone, L. Broggini, C. Visentin, D. Erba, F. Bačić Toplek, K. Peqini, S. Pellegrino, S. Ricagno, C. Paissoni, C. Camilloni. - In: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. - ISSN 0027-8424. - 119:26(2022 Jun 28), pp. e2203181119.1-e2203181119.10. [10.1073/pnas.2203181119]

Multi-eGO: An in silico lens to look into protein aggregation kinetics at atomic resolution

E. Scalone
Primo
;
L. Broggini
Secondo
;
C. Visentin;K. Peqini;S. Pellegrino;S. Ricagno
;
C. Paissoni
Penultimo
;
C. Camilloni
Ultimo
2022

Abstract

Protein aggregation into amyloid fibrils is the archetype of aberrant biomolecular self-assembly processes, with more than 50 associated diseases that are mostly uncurable. Understanding aggregation mechanisms is thus of fundamental importance and goes in parallel with the structural characterization of the transient oligomers formed during the process. Oligomers have been proven elusive to high-resolution structural techniques, while the large sizes and long time scales, typical of aggregation processes, have limited the use of computational methods to date. To surmount these limitations, we here present multi-eGO, an atomistic, hybrid structure-based model which, leveraging the knowledge of monomers conformational dynamics and of fibril structures, efficiently captures the essential structural and kinetics aspects of protein aggregation. Multi-eGO molecular dynamics simulations can describe the aggregation kinetics of thousands of monomers. The concentration dependence of the simulated kinetics, as well as the structural features of the resulting fibrils, are in qualitative agreement with in vitro experiments carried out on an amyloidogenic peptide from Transthyretin, a protein responsible for one of the most common cardiac amyloidoses. Multi-eGO simulations allow the formation of primary nuclei in a sea of transient lower-order oligomers to be observed over time and at atomic resolution, following their growth and the subsequent secondary nucleation events, until the maturation of multiple fibrils is achieved. Multi-eGO, combined with the many experimental techniques deployed to study protein aggregation, can provide the structural basis needed to advance the design of molecules targeting amyloidogenic diseases.
aggregation kinetics; amyloids; molecular dynamics; protein aggregation; structure-based models;
Settore FIS/07 - Fisica Applicata(Beni Culturali, Ambientali, Biol.e Medicin)
Settore BIO/10 - Biochimica
   PIANO DI SOSTEGNO ALLA RICERCA 2015-2017 - TRANSITION GRANT LINEA 1A PROGETTO "UNIMI PARTENARIATI H2020"
   MolAL

   Protein misfolding in AL amyloidosis: from fibrillar deposits to soluble toxicity
   MolAL
   MINISTERO DELL'ISTRUZIONE E DEL MERITO
   20207XLJB2_001
28-giu-2022
23-giu-2022
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/932114
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