Journal article
A Simple PB/LIE Free Energy Function Accurately Predicts the Peptide Binding Specificity of the Tiam1 PDZ Domain
Frontiers in molecular biosciences, Vol.4, pp.65-65
09/26/2017
DOI: 10.3389/fmolb.2017.00065
PMCID: PMC5623046
PMID: 29018806
Abstract
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 α 2 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.
Details
- Title: Subtitle
- A Simple PB/LIE Free Energy Function Accurately Predicts the Peptide Binding Specificity of the Tiam1 PDZ Domain
- Creators
- Nicolas Panel - Laboratoire de Biochimie de l'Ecole polytechniqueYoung Sun - University of Iowa [Iowa City]Ernesto Fuentes - University of Iowa [Iowa City]Thomas Simonson - Laboratoire de Biochimie de l'Ecole polytechnique
- Resource Type
- Journal article
- Publication Details
- Frontiers in molecular biosciences, Vol.4, pp.65-65
- DOI
- 10.3389/fmolb.2017.00065
- PMID
- 29018806
- PMCID
- PMC5623046
- NLM abbreviation
- Front Mol Biosci
- ISSN
- 2296-889X
- eISSN
- 2296-889X
- Publisher
- Frontiers Media
- Grant note
- DOI: 10.13039/100000968, name: American Heart Association, award: 15GRNT25740021
- Language
- English
- Date published
- 09/26/2017
- Academic Unit
- Biochemistry and Molecular Biology
- Record Identifier
- 9984024513302771
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