Unveiling Medin Folding and Dimerization Dynamics and Conformations via Atomistic Discrete Molecular Dynamics Simulations

Abstract

Medin is a principal component of localized amyloid found in the vasculature of individuals over 50 years old. Its amyloid aggregation has been linked to endothelial dysfunction and vascular inflammation, contributing to the pathogenesis of various vascular diseases. Despite its significance, the structures of the medin monomer, oligomer, and fibril remain elusive, and the dynamic processes of medin aggregation are not fully understood. In this study, we comprehensively investigated the medin folding and dimerization dynamics and conformations using atomistic discrete molecular dynamics simulations. Our simulation results suggested that the folding initiation of the medin involved the formation of β-sheets around medin 30−41 and medin 42−50 , with subsequent capping of other segments to their β-sheet edges. Medin monomers typically consisted of three or four β-strands, along with a dynamic N-terminal helix. Two isolated medin peptides readily aggregated into a β-sheet-rich dimer, displaying a strong aggregation propensity. Dimerization of medin not only enhanced the β-sheet conformations but also led to the formation of β-barrel oligomers. The aggregation tendencies of medin 1−18 and medin 19−29 were relatively weak. However, the segments of medin 30−41 and medin 42−50 played a crucial role as they primarily formed a β-sheet core and facilitated medin 1−18 and medin 19−29 to form intra-and interpeptide β-sheets. The findings highlight the critical role of the medin 30−41 and medin 42−50 regions in stabilizing the monomer structure and driving the medin amyloid aggregation. These regions could potentially serve as promising targets for designing antiamyloid inhibitors against amyloid aggregation of medin. Additionally, our study provides a full picture of the monomer conformations and dimerization dynamics for medin, which will help better understand the pathology of medin aggregation.

Computational Investigation of Coaggregation and Cross-Seeding between Aβ and hIAPP Underpinning the Cross-Talk in Alzheimer’s Disease and Type 2 Diabetes

“…A recent study directly illustrated that the creation of a β-barrel oligomer caused membrane leakage in in silico . The formation of β-barrel intermediates was also supported in the aggregation of full-length Aβ, , hIAPP, , human calcitonin (hCT), , and medin in silico and in vitro . The β-barrel structure formed by full-length Aβ was also determined by a cryo-EM assay .…”

“…The β-barrel oligomer, initially discovered in an 11-residue segment of αB-crystallin and frequently observed in toxic amyloid fragments and full-length peptide aggregation simulations, ,,, was proposed as a potentially cytotoxic oligomer in amyloidosis. Our prior simulation studies have demonstrated that the β-barrel oligomer was a common intermediate in the fibrillization of toxic amyloid segments (e.g., NACore, hIAPP 8–20 , hIAPP 19–29 , SOD1 28–38 ) but absent in the aggregation of nontoxic amyloid fragments (e.g., hIAPP 15–25 , SOD1 28–38 G33W39 , SOD1 28–38 G33V39 ).…”

“…To explore the cross-talk between Aβ and hIAPP in amyloid aggregation, we conducted computational studies on the coaggregation of three Aβ peptides with three hIAPP peptides and the cross-seeding dynamics of Aβ monomers interacting with hIAPP fibrils, and vice versa, using atomistic discrete molecular dynamics (DMD) simulations. DMD, a rapid and predictive molecular dynamics algorithm, has been extensively employed in studying protein folding, misfolding, and amyloid aggregation. − Our simulations revealed that three Aβ and three hIAPP peptides spontaneously coaggregated into β-sheet-rich heterocomplexes, including β-barrel oligomers. Intriguingly, the coaggregation of Aβ and hIAPP did not hinder their ability to recruit additional peptides, thereby facilitating the growth of larger aggregates rich in β-sheet structures.…”

“…Therefore, targeting the elongation edges around the amyloidogenic core region could serve as a promising strategy to modulate the pathological aggregation of amyloid proteins in degenerative diseases because the binding-induced extending or capping is not highly sensitive to the amino sequence of the template peptides. 44,48,49…”

Molecular Insights into the Effects of F16L and F19L Substitutions on the Conformation and Aggregation Dynamics of Human Calcitonin

“…These evaluations were conducted using standard MD simulations employing an explicit solvent model in previous investigations. , Furthermore, recent simulations encompassing amyloid aggregation phenomena, including those of calcitonin peptides (hCT, sCT, phCT, DM-hCT, and TL-hCT) , and amylin peptides (hIAPP, hIAPP­(S20G), and rIAPP), ,, have successfully mirrored experimentally observed variations in amyloid propensity and secondary structures. Given its rapid computational speed and improved sampling efficiency, DMD has emerged as a popular tool for investigating protein folding and aggregation dynamics, both within our research group − and in the broader scientific community. − …”