Conformational and energy evaluations of novel peptides binding to dengue virus envelope protein

Transparent Connolly surface representation of peptide DN58opt (yellow) at the binding site. [Display omitted] •Docking and molecular dynamics simulations are used to determine binding affinity.•Van der Waals and electrostatic interactions stabilize the complexes.•Calculated binding free energies correlate well with the experimental Kd values.•Amino acids important for peptide binding to dengue E-protein are identified.•Described methods expedite identification of potential E-protein peptide inhibitors. Effective novel peptide inhibitors which targeted the domain III of the dengue envelope (E) protein by blocking dengue virus (DENV) entry into target cells, were identified. The binding affinities of these peptides towards E-protein were evaluated by using a combination of docking and explicit solvent molecular dynamics (MD) simulation methods. The interactions of these complexes were further investigated by using the Molecular Mechanics-Poisson Boltzmann Surface Area (MMPBSA) and Molecular Mechanics Generalized Born Surface Area (MMGBSA) methods. Free energy calculations of the peptides interacting with the E-protein demonstrated that van der Waals (vdW) and electrostatic interactions were the main driving forces stabilizing the complexes. Interestingly, calculated binding free energies showed good agreement with the experimental dissociation constant (Kd) values. Our results also demonstrated that specific residues might play a crucial role in the effective binding interactions. Thus, this study has demonstrated that a combination of docking and molecular dynamics simulations can accelerate the identification process of peptides as potential inhibitors of dengue virus entry into host cells.