Systemic light chain
amyloidosis (AL) causes a malignant pathology associated with the formation of
amyloid fibrils that deposit in human organs and tissues, leading to dysfunction and severe morbidity.
Amyloid fibril-reactive
antibodies have been used to remove
amyloid from organs and are effective in restoring organ function in patients with
AL amyloidosis. Unfortunately,
antibodies do not bind
amyloid in all AL patients, nor do they efficiently bind many other forms of
amyloid. Recently, a synthetic
peptide P62 was developed, which binds many forms of systemic
amyloidosis and can be further modified and fused to a high-affinity
peptide epitope to expand its utility as a novel
amyloid immunotherapeutic. However, the molecular-level details of P62-fibril binding mechanisms, critical for future
peptide design, are unclear. Here, we combine
protein docking, all-atom molecular dynamics simulation and umbrella sampling to study the dynamical interactions between
peptide P62 and a structural model of the λ light chain in systemic
amyloidosis. We found that P62 only binds to the canonical interface of the fibril where the
peptide inserts into the fibril groove and its two termini are more mobile than the helix core. Our results also revealed an important role of the
lysine residues of P62 in the binding process by forming initial contacts with aspartic
acids on the fibril surface. Collectively, our computational study provided molecular-level insights into the binding mechanism between an
amyloid fibril model and
peptide P62, which could lay a foundation for rational design of
peptides for improved
amyloid diagnosis and
immunotherapy.