RT Journal Article
SR Electronic
T1 Interhelical E@<em>g</em>-N@<em>a</em> Interactions Modulate Coiled Coil Stability within a <em>De Novo</em> Set of Orthogonal Peptide Heterodimers
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2023.05.23.541579
DO 10.1101/2023.05.23.541579
A1 Anthony R. Perez
A1 Yumie Lee
A1 Michael E. Colvin
A1 Andrea D. Merg
YR 2023
UL http://biorxiv.org/content/early/2023/05/23/2023.05.23.541579.abstract
AB The designability of orthogonal coiled coil (CC) dimers, which draw on well-established design rules, plays a pivotal role in fueling the development of CCs as synthetically versatile assembly-directing motifs for the fabrication of bionanomaterials. Here, we aim to expand the synthetic CC toolkit through establishing a “minimalistic” set of orthogonal, de novo CC peptides that comprise 3.5 heptads in length and a single buried Asn to prescribe dimer formation. The designed sequences display excellent partner fidelity, confirmed via circular dichroism (CD) spectroscopy, and are corroborated in silico using molecular dynamics (MD) simulation. Detailed analysis of the MD conformational data highlights the importance of interhelical E@g-N@a interactions in coordinating an extensive 6-residue hydrogen bonding network that “locks” the interchain Asn-Asn’ contact in place. The enhanced stability imparted to the Asn-Asn’ bond elicits an increase in thermal stability of CCs up to ∼15°C and accounts for significant differences in stability within the collection of similarly designed orthogonal CC pairs. The presented work underlines the utility of MD simulation as a tool for constructing de novo, orthogonal CCs, and presents an alternative handle for modulating the stability of orthogonal CCs via tuning the number of interhelical E@g-N@a contacts. Expansion of CC design rules is a key ingredient for guiding the design and assembly of more complex, intricate CC-based architectures for tackling a variety of challenges within the fields of nanomedicine and bionanotechnology.Competing Interest StatementThe authors have declared no competing interest.