Folding Intermediates, Heterogeneous Native Ensembles and Protein Function.
J Mol Biol
; 433(24): 167325, 2021 12 03.
Article
en En
| MEDLINE
| ID: mdl-34695380
ABSTRACT
Single domain proteins fold via diverse mechanisms emphasizing the intricate relationship between energetics and structure, which is a direct consequence of functional constraints and demands imposed at the level of sequence. On the other hand, elucidating the interplay between folding mechanisms and function is challenging in large proteins, given the inherent shortcomings in identifying metastable states experimentally and the sampling limitations associated with computational methods. Here, we show that free energy profiles and surfaces of large systems (>150 residues), as predicted by a statistical mechanical model, display a wide array of folding mechanisms with ubiquitous folding intermediates and heterogeneous native ensembles. Importantly, residues around the ligand binding or enzyme active site display a larger tendency to partially unfold and this manifests as intermediates or excited states along the folding coordinate in ligand binding domains, transcription repressors, and representative enzymes from all the six classes, including the SARS-CoV-2 receptor binding domain (RBD) of the spike protein and the protease Mpro. It thus appears that it is relatively easier to distill the imprints of function on the folding landscape of larger proteins as opposed to smaller systems. We discuss how an understanding of energetic-entropic features in ordered proteins can pinpoint specific avenues through which folding mechanisms, populations of partially structured states and function can be engineered.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Conformación Proteica
/
Modelos Moleculares
/
Pliegue de Proteína
/
Enzimas
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
J Mol Biol
Año:
2021
Tipo del documento:
Article