%A Panel,Nicolas %A Sun,Young Joo %A Fuentes,Ernesto J. %A Simonson,Thomas %D 2017 %J Frontiers in Molecular Biosciences %C %F %G English %K molecular dynamics,continuum electrostatics,NAMD SOFTWARE,fluorescence anisotropy,peptide design %Q %R 10.3389/fmolb.2017.00065 %W %L %M %P %7 %8 2017-September-26 %9 Original Research %+ Ernesto J. Fuentes,Department of Biochemistry, Roy J. and Lucille A. Carver College of Medicine, University of Iowa,United States,ernesto-fuentes@uiowa.edu %+ Ernesto J. Fuentes,Holden Comprehensive Cancer Center,United States,ernesto-fuentes@uiowa.edu %+ Thomas Simonson,Laboratoire de Biochimie (CNRS UMR7654), Ecole Polytechnique,France,thomas.simonson@polytechnique.fr %# %! A PB/LIE free energy function accurately predicts PDZ-peptide binding specificity %* %< %T A Simple PB/LIE Free Energy Function Accurately Predicts the Peptide Binding Specificity of the Tiam1 PDZ Domain %U https://www.frontiersin.org/articles/10.3389/fmolb.2017.00065 %V 4 %0 JOURNAL ARTICLE %@ 2296-889X %X PDZ domains generally bind short amino acid sequences at the C-terminus of target proteins, and short peptides can be used as inhibitors or model ligands. Here, we used experimental binding assays and molecular dynamics simulations to characterize 51 complexes involving the Tiam1 PDZ domain and to test the performance of a semi-empirical free energy function. The free energy function combined a Poisson-Boltzmann (PB) continuum electrostatic term, a van der Waals interaction energy, and a surface area term. Each term was empirically weighted, giving a Linear Interaction Energy or “PB/LIE” free energy. The model yielded a mean unsigned deviation of 0.43 kcal/mol and a Pearson correlation of 0.64 between experimental and computed free energies, which was superior to a Null model that assumes all complexes have the same affinity. Analyses of the models support several experimental observations that indicate the orientation of the α2 helix is a critical determinant for peptide specificity. The models were also used to predict binding free energies for nine new variants, corresponding to point mutants of the Syndecan1 and Caspr4 peptides. The predictions did not reveal improved binding; however, they suggest that an unnatural amino acid could be used to increase protease resistance and peptide lifetimes in vivo. The overall performance of the model should allow its use in the design of new PDZ ligands in the future.