Heparin-Assisted Amyloidogenesis Uncovered through Molecular Dynamics Simulations

Khurshid, Beenish and Rehman, Ashfaq Ur and Luo, Ray and Khan, Alamzeb and Wadood, Abdul and Anwar, Jamshed (2022) Heparin-Assisted Amyloidogenesis Uncovered through Molecular Dynamics Simulations. ACS Omega, 7 (17). pp. 15132-15144. ISSN 2470-1343

Abstract

Glycosaminoglycans (GAGs), in particular, heparan sulfate and heparin, are found colocalized with Aβ amyloid. They have been shown to enhance fibril formation, suggesting a possible pathological connection. We have investigated heparin’s assembly of the KLVFFA peptide fragment using molecular dynamics simulation, to gain a molecular-level mechanistic understanding of how GAGs enhance fibril formation. The simulations reveal an exquisite process wherein heparin accelerates peptide assembly by first “gathering” the peptide molecules and then assembling them. Heparin does not act as a mere template but is tightly coupled to the peptides, yielding a composite protofilament structure. The strong intermolecular interactions suggest composite formation to be a general feature of heparin’s interaction with peptides. Heparin’s chain flexibility is found to be essential to its fibril promotion activity, and the need for optimal heparin chain length and concentration has been rationalized. These insights yield design rules (flexibility; chain-length) and protocol guidance (heparin:peptide molar ratio) for developing effective heparin mimetics and other functional GAGs.