Designing Short Peptides with High Affinity for Organic Molecules: A Combined Docking, Molecular Dynamics, And Monte Carlo Approach

We present a method for designing artificial receptors
capable
of binding with high affinity to a chosen target organic molecule.
The primary sequence of the peptide is optimized to maximize its binding
affinity. Our algorithm builds on a combination of molecular dynamics,
semiflexible docking, and replica exchange Monte Carlo and performs
simultaneous sampling in sequence and conformational spaces carefully
selecting the degree of flexibility in the mutated peptides. The approach
is used to design a decapeptide able to bind efavirenz. The calculated
binding energy of the designed peptide (approximately −12 kcal/mol)
was confirmed experimentally by fluorescence measurements. NMR spectroscopy
confirmed the interactions between the peptide and the efavirenz molecule
predicted by the algorithm.