Molecular dynamics to identify key residues in disordered protein complexes

BASTIEN, MC; TAVOLARO, FG; MARINO-BUSLJE C; FERNÁNDEZ, ML

Rosario

Congreso; XIII Argentine Congress of Bioinformatics and Computational Biology. XIII International Conference of the Iberoamerican Society of Bioinformatics. III Annual Meeting of the Ibero-American Artificial Intelligence Network for Big BioData; 2023

Background: Nuclear Magnetic Resonance (NMR) spectroscopy has longbeen a valuable tool for characterizing intrinsically disorderedproteins (IDPs) molecular conformations, yet it often provideslimited information about structural conformation of their complexes.These proteins are associated with several key biological processes,therefore their malfunction could trigger diseases such ascáncer,Parkinson, Alhzeimer, etc. In this study, we address the challenge ofincreasing the conformational information from NMR data tocharacterize IDPs complexes, by employing molecular dynamicssimulations (MD). The NMR technique results in an ensemble ofstructures, whereas MD provides information on the behavior of thecomplexes over time, improving our understanding oftheirstructural dynamics.Results: Our investigation involved 9protein-protein complexes, for each one, 2 MD simulations wereperformed using two different NMR conformers (complexes) as startingpoints. In a second stage, the results were analyzed revealing thateach complex exhibits residue interactions with varying probabilitiestogether with a wide range of conformational states. Notably, weidentified core interactions within these complexes, shedding lighton the key factors that influence their stability and eventually,their functionality. Furthermore, we identified 3 complexes where theproteins separated enough to lose the core interactions, more datawill be needed to determine if the function associated requires thesecomplexes to be transient or labile.Conclusion: Ourfindings demonstrate that molecular dynamics simulations complementNMR data by providing a more comprehensive view of complexstructures. The molecular dynamics approach refines the informationobtained from NMR, yielding a more accurate count of core contactswithin a protein-protein interaction over time. Moreover, our studyhighlights the pivotal role of specific residues in maintaining thestability and integrity of complex interactions. Overall, thecombination of NMR and molecular dynamics proves to be a powerfulstrategy for unraveling the intricacies of biomolecular complexes.Taken together, this study allows for a deeper understanding of thebehavior and function of IDP complexes and eventually, thisinformation could be used to explore new disease treatmentstrategies.p { line-height: 115%; margin-bottom: 0.25cm; background: transparent }