Computer-aided design of amino acid-based therapeutics: a review

Farhadi, Tayebeh; Hashemian, Seyed MohammadReza

To decrease the degrees of freedom for each amino acid and searching the sequence space, diverse approaches such as hydrophobic patterning have been proposed. 58 Monomers can be used to probe a protein structure 59 and improve its function, 60 other than the naturally occurring amino acids. 61 Sampling of side chain conformational space to form conformations Side chain conformations are typically consistent with the energy minima of molecular potentials and can be obtained from a structural database. 62 Rotamer statuses are related to the repeatedly detected values of dihedral angles in the side chain of each amino acid. For example, the simplest amino acids including alanine and glycine have only one rotamer status, while the bigger amino acids have .80 diverse rotamer statuses. 62 A variety of rotamer libraries including backbonedependent, secondary structure-dependent and backboneindependent libraries have been developed for protein design. 62, 63 By using a rotamer library, one can discretize a meaningful state space to decrease the computational difficulty. Rotamer libraries can be extended beyond the 20 natural amino acids. The effective rotamers can model cofactors, ligands, water and posttranslational modifications. For example, to improve the modeling of protein-protein interactions and model water within proteins interiors, the structurally definite water molecules can be inserted as a solvated rotamer library. 61