期刊
BIOPHYSICAL CHEMISTRY
卷 286, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.bpc.2022.106805
关键词
Amyloid inhibition; Non-canonical amino acids; Protein design; MD simulations
资金
- National Institute on Aging, NIH [R03 AG058100]
- Artie McFerrin Department of Chemical Engineering at Texas AM University
- Texas A&M University Graduate Diversity Fellowship from the TAMU Office of Graduate and Professional Studies
This study computationally investigated the possibility of enhancing the anti-amyloid properties of beta-wrapin AS10 by redesigning its currently non-functional N-terminal domain. The simulations suggest that the redesigned N-terminal domain can bind to A beta fibrils and simultaneously maintain its sequestering properties for A beta monomers.
beta-wrapins are engineered binding proteins of which different mutants can bind and sequester amyloidogenic proteins amyloid-beta (A beta), islet amyloid polypeptide (IAPP), and alpha-synuclein (alpha-syn), thereby inhibiting their aggregation into amyloid fibrils. beta-wrapin AS10 is capable of binding and sequestering all three amyloidogenic monomers with micro-molar affinity, with its N-terminal domains remaining flexible and non-functional. Here, we computationally investigated the hypothesis that the anti-amyloid properties of AS10 can be amplified by redesigning its currently non-functional N-terminal domain with particular combinations of canonical and noncanonical amino acids (ncAAs) that can mimic the binding and inhibitory anti-amyloid function of curcumin, using a combination of molecular docking and molecular dynamics simulations. Our simulations suggest that the inhibitory mechanism attributed to the binding of the computationally designed AS10 N-terminal domain to the A beta fibril can act simultaneously to its sequestering properties for A beta which are attributed to the core of AS10. Thus, our study proposes that the N-terminal domain of AS10 can be further modified to amplify its anti-amyloid properties, resulting in a beta-wrapin that may simultaneously prohibit elongation to existing amyloid fibrils and also sequester amyloid monomers.
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