Decreased Interactions between Calmodulin and a Mutant Huntingtin Model Might Reduce the Cytotoxic Level of Intracellular Ca2+: A Molecular Dynamics Study

Abstract

Mutant huntingtin (m-HTT) proteins and calmodulin (CaM) co-localize in the cerebral cortex with significant effects on the intracellular calcium levels by altering the specific calcium-mediated signals. Furthermore, the mutant huntingtin proteins show great affinity for CaM that can lead to a further stabilization of the mutant huntingtin aggregates. In this context, the present study focuses on describing the interactions between CaM and two huntingtin mutants from a biophysical point of view, by using classical Molecular Dynamics techniques. The huntingtin models consist of a wild-type structure, one mutant with 45 glutamine residues and the second mutant with nine additional key-point mutations from glutamine residues into proline residues (9P(EM) model). Our docking scores and binding free energy calculations show higher binding affinities of all HTT models for the C-lobe end of the CaM protein. In terms of dynamic evolution, the 9P(EM) model triggered great structural changes into the CaM protein’s structure and shows the highest fluctuation rates due to its structural transitions at the helical level from α-helices to turns and random coils. Moreover, our proposed 9P(EM) model suggests much lower interaction energies when compared to the 45Qs-HTT mutant model, this finding being in good agreement with the 9P(EM)’s antagonistic effect hypothesis on highly toxic protein–protein interactions.

Small-Molecule Disruptors of Mutant Huntingtin–Calmodulin Protein–Protein Interaction Attenuate Deleterious Effects of Mutant Huntingtin

“…Abnormal protein–protein interactions are associated with various diseases such as cancers and neurodegenerative diseases. , Targeting the abnormal protein–protein interactions and thereby normalizing protein function are important strategies for developing therapeutics to treat diseases. Previous studies in our lab and others have identified an abnormal protein–protein interaction between mHTT and calmodulin (CaM). − mHTT from HD patients bound to CaM with higher affinity compared to wild-type HTT from postmortem brain tissue . Studies conducted in our lab found that CaM is present in intranuclear inclusions and co-localizes with HTT, transglutaminase, and transglutaminase-induced cross-links within the nucleus of postmortem cortical tissue from HD patients .…”

Unveiling sultam in drug discovery: spotlight on the underexplored scaffold

“…Protein-protein interaction (PPI) between calmodulin and mutant huntingtin protein has been shown to contribute to the progression of Huntington's disease (HD). 66,67 Using the high-throughput AlphaScreen platform, Klus et al 68 discovered a series of sultams (Fig. 26) as potent smallmolecule PPI disruptors.…”

Reviewing the Structure–Function Paradigm in Polyglutamine Disorders: A Synergistic Perspective on Theoretical and Experimental Approaches

“…The study proposes a threshold of nine proline residues for significant helical disruption rates and emphasizes the need for further dynamic investigations to understand the interactions of these novel mutant models with other cellular counterparts. A year later, the authors built on their previous work [ 257 ] by further exploring the interactions between mHTT models and calmodulin (CaM) [ 258 ]. This time, the authors investigated how their previously developed mHTT models, especially those with key-point mutations (such as the 9P(EM)), interact with CaM.…”

“…This time, the authors investigated how their previously developed mHTT models, especially those with key-point mutations (such as the 9P(EM)), interact with CaM. The findings suggest that these mutant models show different binding affinities, total interaction energies and induce distinct structural changes within CaM’s structure [ 258 ]. Consequently, this research enhances our understanding of mHTT–CaM complexes and their implications in HD, offering insights into potential therapeutic strategies targeting these interactions.…”

“…Their findings suggest that disrupting the binding of mHTT to CaM could be a promising approach for developing therapeutics for HD [ 324 ]. It is worth emphasizing the correlations between this particular study and the all-atom study focused on mHTT–CaM interactions [ 258 ], previously described in Section 5.2 . Although the methodologies differ, computational simulations versus experimental observation, the core focus remains consistent: understanding the intricate dynamics of mHTT and identifying potential means of ‘breaking’ mHTT–CaM bindings (either via additional mHTT mutations [ 258 ] or via the development of small molecular disruptors [ 324 ]), known for their protective effects against polyQ-related cytotoxicity.…”