Computational identification of self‐inhibitory peptides from envelope proteins

Abstract Fusion process is known to be the initial step of viral infection and hence targeting the entry process is a promising strategy to design antiviral therapy. The self‐inhibitory peptides derived from the enveloped (E) proteins function to inhibit the protein–protein interactions in the membrane fusion step mediated by the viral E protein. Thus, they have the potential to be developed into effective antiviral therapy. Herein, we have developed a Monte Carlo‐based computational method with the aim to identify and optimize potential peptide hits from the E proteins. The stability of the peptides, which indicates their potential to bind in situ to the E proteins, was evaluated by two different scoring functions, dipolar distance‐scaled, finite, ideal‐gas reference state and residue‐specific all‐atom probability discriminatory function. The method was applied to α‐helical Class I HIV‐1 gp41, β‐sheet Class II Dengue virus (DENV) type 2 E proteins, as well as Class III Herpes Simplex virus‐1 (HSV‐1) glycoprotein, a E protein with a mixture of α‐helix and β‐sheet structural fold. The peptide hits identified are in line with the druggable regions where the self‐inhibitory peptide inhibitors for the three classes of viral fusion proteins were derived. Several novel peptides were identified from either the hydrophobic regions or the functionally important regions on Class II DENV‐2 E protein and Class III HSV‐1 gB. They have potential to disrupt the protein–protein interaction in the fusion process and may serve as starting points for the development of novel inhibitors for viral E proteins. Proteins 2012; © 2012 Wiley Periodicals, Inc.