Journal article
Accurate PDZ/Peptide Binding Specificity with Additive and Polarizable Free Energy Simulations
Biophysical journal, Vol.114(5), pp.1091-1102
03/13/2018
DOI: 10.1016/j.bpj.2018.01.008
PMCID: PMC5883551
PMID: 29539396
Abstract
PDZ domains contain 80-100 amino acids and bind short C-terminal sequences of target proteins. Their specificity is essential for cellular signaling pathways. We studied the binding of the Tiam1 PDZ domain to peptides derived from the C-termini of its Syndecan-1 and Caspr4 targets. We used free energy perturbation (FEP) to characterize the binding energetics of one wild-type and 17 mutant complexes by simulating 21 alchemical transformations between pairs of complexes. Thirteen complexes had known experimental affinities. FEP is a powerful tool to understand protein/ligand binding. It depends, however, on the accuracy of molecular dynamics force fields and conformational sampling. Both aspects require continued testing, especially for ionic mutations. For six mutations that did not modify the net charge, we obtained excellent agreement with experiment using the additive, AMBER ff99SB force field, with a root mean square deviation (RMSD) of 0.37 kcal/mol. For six ionic mutations that modified the net charge, agreement was also good, with one large error (3 kcal/mol) and an RMSD of 0.9 kcal/mol for the other five. The large error arose from the overstabilization of a protein/peptide salt bridge by the additive force field. Four of the ionic mutations were also simulated with the polarizable Drude force field, which represents the first test of this force field for protein/ligand binding free energy changes. The large error was eliminated and the RMS error for the four mutations was reduced from 1.8 to 1.2 kcal/mol. The overall accuracy of FEP indicates it can be used to understand PDZ/peptide binding. Importantly, our results show that for ionic mutations in buried regions, electronic polarization plays a significant role.
Details
- Title: Subtitle
- Accurate PDZ/Peptide Binding Specificity with Additive and Polarizable Free Energy Simulations
- Creators
- Nicolas Panel - Laboratoire de Biochimie de l'Ecole polytechniqueFrancesco Villa - Laboratoire de Biochimie de l'Ecole polytechniqueErnesto Fuentes - University of Iowa [Iowa City]Thomas Simonson - Laboratoire de Biochimie de l'Ecole polytechnique
- Resource Type
- Journal article
- Publication Details
- Biophysical journal, Vol.114(5), pp.1091-1102
- Publisher
- Biophysical Society
- DOI
- 10.1016/j.bpj.2018.01.008
- PMID
- 29539396
- PMCID
- PMC5883551
- ISSN
- 0006-3495
- eISSN
- 1542-0086
- Language
- English
- Date published
- 03/13/2018
- Academic Unit
- Biochemistry and Molecular Biology
- Record Identifier
- 9984024517902771
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