title: Introducing folding stability into the score function for computational design of RNA-binding peptides boosts the probability of success.
abstract: A computational strategy that integrates our peptide search algorithm with atomistic molecular dynamics simulation was used to design rational peptide drugs that recognize and bind to the anticodon stem and loop domain (ASL(Lys3)) of human tRNAUUULys3 for the purpose of interrupting HIV replication. The score function of the search algorithm was improved by adding a peptide stability term weighted by an adjustable factor λ to the peptide binding free energy. The five best peptide sequences associated with five different values of λ were determined using the search algorithm and then input in atomistic simulations to examine the stability of the peptides' folded conformations and their ability to bind to ASL(Lys3). Simulation results demonstrated that setting an intermediate value of λ achieves a good balance between optimizing the peptide's binding ability and stabilizing its folded conformation during the sequence evolution process, and hence leads to optimal binding to the target ASL(Lys3). Thus, addition of a peptide stability term significantly improves the success rate for our peptide design search.
authors.affiliation: Chemical and Biomolecular Engineering Department, North Carolina State University, Raleigh, North Carolina, 27695-7905.
authors.forename: Xingqing
authors.initials: X
authors.lastname: Xiao
authors.affiliation: The RNA Institute, University at Albany, State University of New York, Albany, New York, 12222.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Agris
authors.affiliation: Chemical and Biomolecular Engineering Department, North Carolina State University, Raleigh, North Carolina, 27695-7905.
authors.forename: Carol K
authors.initials: CK
authors.lastname: Hall
mesh_terms: D000465:Algorithms; D019295:Computational Biology / Q000379:methods*; D015195:Drug Design; D006801:Humans; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017510:Protein Folding; D055550:Protein Stability; D012357:RNA, Transfer, Lys / Q000737:chemistry / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D010455:Peptides; D012357:RNA, Transfer, Lys; D016601:RNA-Binding Proteins
keywords: atomistic molecular dynamics simulation; binding affinity and specificity; peptide design; search algorithm; tRNALys3UUU