ArticleBiophysical journal2018
Accurate PDZ/Peptide Binding Specificity with Additive and Polarizable Free Energy Simulations.
Article in Biophysical journal, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed.
- Article
- Relative Binding Free Energy Estimation of Congeneric Ligands and Macromolecular Mutants with the Alchemical Transfer Method with Coordinate Swapping.Journal of chemical information and modeling · 2025Article
- Binding Selectivity Analysis from Alchemical Receptor Hopping and Swapping Free Energy Calculations.The journal of physical chemistry. B · 2024Article
- System-Specific Parameter Optimization for Nonpolarizable and Polarizable Force Fields.Journal of chemical theory and computation · 2024Article
- What to Make of Zero: Resolving the Statistical Noise from Conformational Reorganization in Alchemical Binding Free Energy Estimates with Metadynamics Sampling.Journal of chemical theory and computation · 2024Article
- Article
- EnCPdock: a web-interface for direct conjoint comparative analyses of complementarity and binding energetics in inter-protein associations.Journal of molecular modeling · 2023Article
- Additive energetic contributions of multiple peptide positions determine the relative promiscuity of viral and human sequences for PDZ domain targets.Protein science : a publication of the Protein Society · 2023Article
- The Drug-Induced Interface That Drives HIV-1 Integrase Hypermultimerization and Loss of Function.mBio · 2023Article
- Alchemical Free Energy Calculations to Investigate Protein-Protein Interactions: the Case of the CDC42/PAK1 Complex.Journal of chemical information and modeling · 2022Article
- Dawn of a New Era for Membrane Protein Design.Biodesign research · 2022Review
- Modelling peptide-protein complexes: docking, simulations and machine learning.QRB discovery · 2022Article
- Free Energy-Based Computational Methods for the Study of Protein-Peptide Binding Equilibria.Methods in molecular biology (Clifton, N.J.) · 2022Article
- A Fluorescence-Based Assay to Determine PDZ-Ligand Binding Thermodynamics.Methods in molecular biology (Clifton, N.J.) · 2021Article
- Computational Design of PDZ-Peptide Binding.Methods in molecular biology (Clifton, N.J.) · 2021Article
- Statistical mechanics of polarizable force fields based on classical Drude oscillators with dynamical propagation by the dual-thermostat extended Lagrangian.The Journal of chemical physics · 2020Article
- Improved Modeling of Cation-π and Anion-Ring Interactions Using the Drude Polarizable Empirical Force Field for Proteins.Journal of computational chemistry · 2020Article
- Rapid and accurate structure-based therapeutic peptide design using GPU accelerated thermodynamic integration.Proteins · 2019Article
- Classical Drude Polarizable Force Field Model for Methyl Phosphate and Its Interactions with MgThe journal of physical chemistry. A · 2018Article
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4 authors.
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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.
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