This presentation addresses the fundamental challenge of understanding how hydrophobic interactions are encoded by chemical nanopatterns, using sequences of peptides found in coronavirus (CoV) spike proteins as an important and relevant context. A critical initial step leading to fusion and infection of SARS-CoV-2 and MERS-CoV virus particles with target host membranes is insertion of the fusion peptide (FP) sequence of the spike protein into the host cell membrane. The FP sequences of SARS-CoV-2 and MERS-CoV, denoted FP1 and FP2, are largely conserved and comprise a mixture of nonpolar and charged residues hypothesized to enable fusion via hydrophobic (lipid-binding) and ionic interactions (mediated by Ca2+). Past studies have identified nonpolar motifs (e.g., leucine-leucine-phenylalanine, “LLF”) of the FP and the presence of Ca2+ to impact fusion activity. However, the role of hydrophobic interactions, as encoded by the FP sequence, and potentially modulated by Ca2+, is not well understood. To explore how the FP sequence encodes hydrophobic interactions, we have recently used single-molecule force measurements to elucidate the role of specific amino acids of FP1 and FP2 in modulating intermolecular interactions with model nonpolar surfaces. This presentation will focus on results obtained with two peptide sequences: First, we will describe single molecule force measurements of a short peptide sequence from FP1 that contains LLF. We will use the measurements to address several key questions: 1) Does LLF play a central role in mediating hydrophobic interactions of SARS-2 FP1 with model surfaces? 2) Is there a difference in the hydrophobic interaction strength between SARS-2 and MERS, where LLF is flanked by distinct residues? Second, we will report single molecule force measurements using a peptide sequence that spans FP1 and FP2, presenting four potential Ca2+ binding sites. We will use the measurements to address the question of whether or not binding of Ca2+ to FP impacts hydrophobic forces encoded by the sequence. The results of our single-molecule force measurements will be placed into the context of independent measurements of fusion peptide activity.

Characterizing the hydrophobic interactions of fusion peptides of coronaviruses using single-molecule force measurements

ACS Fall 2021

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