Structural Heterogeneity of Intermediate States Facilitates CRIPT Peptide Binding to the PDZ3 Domain: Insights from Molecular Dynamics and Markov State Model Analysis.

 0 Người đánh giá. Xếp hạng trung bình 0

Tác giả: Jie Ji, Xingyu Song, Dongdong Wang, Wenning Wang, Jingwei Weng

Ngôn ngữ: eng

Ký hiệu phân loại:

Thông tin xuất bản: United States : Journal of chemical theory and computation , 2025

Mô tả vật lý:

Bộ sưu tập: NCBI

ID: 489343

Intrinsically disordered proteins (IDPs), characterized by a lack of defined tertiary structure, are ubiquitous and indispensable components of cellular machinery. These proteins participate in a diverse array of biological processes, often undergoing conformational transitions upon binding to their target, a phenomenon termed "folding-upon-binding." The finding raises the question of how to achieve rapid binding kinetics in the presence of intrinsic disorder, and the underlying molecular mechanism remains elusive. This study investigated the interaction between the C-terminal region of CRIPT and the third PDZ domain of PSD-95, a critical complex in neuronal development. Upon binding, the CRIPT peptide adopts a β-strand conformation, a process meticulously characterized through extensive molecular dynamics simulations totaling 67.7 μs. Our findings reveal a funnel-like binding landscape in which IDPs can adopt multiple conformations prior to binding, forming structurally heterogeneous intermediate complexes and leading to diverse binding pathways. The stabilization of these intermediate complexes necessitates a dynamic interplay of native and non-native interactions. Markov state model analysis underscores the important role of structural heterogeneity as it contributes to accelerated binding. These findings enrich the classical fly-casting mechanism and provide novel insights into the functional advantages conferred by intrinsic disorder.
Tạo bộ sưu tập với mã QR

THƯ VIỆN - TRƯỜNG ĐẠI HỌC CÔNG NGHỆ TP.HCM

ĐT: (028) 36225755 | Email: tt.thuvien@hutech.edu.vn

Copyright @2024 THƯ VIỆN HUTECH