The Impairment of TorsinA's Binding to and Interactions With Its Activator: An Atomistic Molecular Dynamics Study of Primary Dystonia

Abstract

Primary dystonia's prolonged muscle contractions and the associated abnormal postures and twisting movements remain incurable. Genetic mutation/deletion of GAG from TorsonA's gene resulting in ΔE303 (which weakens the binding between TorsinA and its activator, such as LULL1) primarily cause this neurodegenerative disorder. We studied TorsinA-LULL1 (or TorsinAΔE303-LULL1) bindings and interactions. For the first time, we show the atomic details of TorsinA-LULL1 dynamic interactions and TorsinAΔE303-LULL1 dynamic interactions and their binding affinities. Our results show extensive effects of ΔE303 on TorsinAΔE303-LULL1 interactions, and suggest that the differences between TorsinA-LULL1 interactions and TorsinAΔE303-LULL1 interactions are non-subtle. ΔE303 significantly weakens TorsinAΔE303-LULL1's binding affinity. We present pieces of evidence proving that the effects of ΔE303 (on the differences between TorsinA-LULL1 interactions and TorsinAΔE303-LULL1 interactions) are more pronounced than previously suggested, and that the nanobody used for achieving the X-ray crystallization in the previous study attenuated the differences between TorsinA-LULL1 and TorsinAΔE303-LULL1 interactions. Our accounts of the dynamic interactions between “TorsinA and LULL1” and between “TorsinAΔE303 and LULL1” and the detailed effects of ΔE303 on TorsinA-/TorsinAΔE303-LULL1 build on previous findings and offer new insights for a better understanding of the molecular basis of Primary Dystonia. Our results have long-term potentials of guiding the development of medications for the disease.

Mechanistic Insights into Specific G Protein Interactions with Adenosine Receptors Revealed by Accelerated Molecular Simulations

“…Residue Phe355 (GH5.26) formed close interactions with Lys 6.29 , His 6. 32 and Ser 6. 36 of the A2AAR.…”

“…In this regard, a novel and robust Gaussian accelerated MD (GaMD) method has been developed to allow for unconstrained enhanced sampling and free energy calculations of large biomolecules [26][27][28] . GaMD has been applied to successfully simulate protein folding 26,27 , proteinligand binding and unbinding 26,27,29 , GPCR activation 29 , large-scale conformational transitions of the CRISPR-Cas9 gene-editing system 30 , T cell receptor signaling protein 31 and human dystonia related protein 32 , and so on. Notably, GaMD has been recently applied to capture spontaneous binding of the G-protein mimetic nanobody to a muscarinic GPCR.…”

Agonist Binding and G Protein Coupling in Histamine H2 Receptor: A Molecular Dynamics Study

“…Moreover, because the boost potential exhibits a Gaussian distribution, biomolecular free energy profiles can be properly recovered through cumulant expansion to the second order [ 23 ]. GaMD simulations have successfully revealed mechanisms of protein folding and conformational changes [ 23 , 25 , 26 , 27 , 28 , 29 ], ligand binding [ 23 , 26 , 27 , 30 , 31 , 32 , 33 , 34 , 35 ], and protein-protein/membrane/nucleic acid interactions [ 32 , 36 , 37 , 38 , 39 , 40 ].…”

G‐Protein‐Coupled Receptor–Membrane Interactions Depend on the Receptor Activation State

“…In this context, Gaussian accelerated MD (GaMD) is a robust technique that provides unconstrained enhanced sampling without the need to set predefined collective variables . GaMD simulations have been successfully applied to investigate GPCR activation, protein folding, ligand binding and unbinding, protein–protein interactions, and protein–nucleic acid interactions …”