Viegas, R. G. | Search bioRxiv

bioRxiv2024

ELViM: Understanding Molecular Energy Landscape

AbstractMolecular dynamics (MD) simulations provide a powerful means to explore the dynamic behavior of biomolecular systems at the atomic level. However, analyzing the vast datasets generated by MD simulations poses significant challenges. This manuscript discusses the Energy Landscape Visualization Method (ELViM), a multidimensional reduction technique inspired by energy landscape theory. ELViM transcends one-dimensional representations, offering a comprehensive analysis of the effective conformational phase space without the need for predefined reaction coordinates. We apply ELViM to study the folding landscape of the antimicrobial peptide Polybia-MP1, showcasing its versatility in capturing complex biomolecular dynamics. Using dissimilarity matrices and a force-scheme approach, ELViM provides intuitive visualizations, revealing structural correlations, and local conformational signatures. The method is demonstrated to be adaptable, robust, and applicable to various biomolecular systems.

biophysics↗

bioRxiv2024

Understanding the Energy Landscape of Intrinsically Disordered Protein Ensembles

A substantial portion of various organisms proteomes comprises intrinsically dis-ordered proteins (IDPs) that lack a defined three-dimensional structure. These IDPs exhibit a diverse array of conformations, displaying remarkable spatio-temporal het-erogeneity 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 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.

biophysics↗