posted on 2024-05-07, 15:09authored byRafael
G. Viegas, Ingrid B. S. Martins, Vitor B. P. Leite
A substantial portion of various
organisms’ proteomes
comprises
intrinsically disordered proteins (IDPs) that lack a defined three-dimensional
structure. These IDPs exhibit a diverse array of conformations, displaying
remarkable spatiotemporal heterogeneity and exceptional conformational
flexibility. Characterizing the structure or structural ensemble of
IDPs presents significant conceptual and methodological challenges
owing to the absence of a well-defined native structure. While databases
such as the Protein Ensemble Database (PED) provide IDP ensembles
obtained through a combination of experimental data and molecular
modeling, the absence of reaction coordinates poses challenges in
comprehensively understanding pertinent aspects of the system. In
this study, we leverage the energy landscape visualization method
(JCTC, 6482, 2019) to scrutinize four IDP ensembles sourced from PED.
ELViM, a methodology that circumvents the need for a priori reaction
coordinates, aids in analyzing the ensembles. The specific IDP ensembles
investigated are as follows: two fragments of nucleoporin (NUL: 884-993
and NUS: 1313-1390), yeast sic 1 N-terminal (1-90), and the N-terminal
SH3 domain of Drk (1-59). Utilizing ELViM enables the comprehensive
validation of ensembles, facilitating the detection of potential inconsistencies
in the sampling process. Additionally, it allows for identifying and
characterizing the most prevalent conformations within an ensemble.
Moreover, ELViM facilitates the comparative analysis of ensembles
obtained under diverse conditions, thereby providing a powerful tool
for investigating the functional mechanisms of IDPs.