A Simple PB/LIE Free Energy Function Accurately Predicts the Peptide Binding Specificity of the Tiam1 PDZ Domain

Panel, Nicolas; Sun, Young Joo; Fuentes, Ernesto J.; Simonson, Thomas

doi:10.3389/fmolb.2017.00065

Cited by 11 publications

(17 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Conversely, when ID6 was forced to bind a fibril in a nonextended compact conformation, the calculated interaction energy was more than 35 kcal/mol less favorable than the extended conformation (Figure S14). 59,60 Interaction energies were determined for the entire family of IDs and showed that the longer IDs have greater binding potentials (Figure 6A). Interestingly, the interaction energies are much greater than what might be expected for typical electrostatic interactions in proteins (normally on the order of single digit kcal/mol) 29,30 and are more comparable to the energies observed for the complexation of oppositely charged peptide homopolymers.…”

Section: Results and Discussionmentioning

confidence: 99%

Electrostatically Driven Guanidinium Interaction Domains that Control Hydrogel-Mediated Protein Delivery In Vivo

et al. 2019

View full text Add to dashboard Cite

Protein biologics are an important class of drugs, but the necessity for frequent parenteral administration is a major limitation. Drug-delivery materials offer a potential solution, but protein-material adsorption can cause denaturation, which reduces their effectiveness. Here, we describe a new protein delivery platform that limits direct contact between globular protein domains and material matrix, yet from a single subcutaneous administration can be tuned for long-term drug release. The strategy utilizes complementary electrostatic interactions made between a suite of designed interaction domains (IDs), installed onto the terminus of a protein of interest, and a negatively charged self-assembled fibrillar hydrogel. These intermolecular interactions can be easily modulated by choice of ID to control material interaction and desorption energies, which allows regulation of protein release kinetics to fit desired release profiles. Molecular dynamics studies provided a molecular-level understanding of the mechanisms that govern release and identified optimal binding zones on the gel fibrils that facilitate strong ID–material interactions, which are crucial for sustained release of protein. This delivery platform can be easily loaded with cargo, is shear-thin syringe implantable, provides improved protein stability, is capable of a diverse range of in vitro release rates, and most importantly, can accomplish long-term control over in vivo protein delivery.

show abstract

Section: Results and Discussionmentioning

confidence: 99%

Electrostatically Driven Guanidinium Interaction Domains that Control Hydrogel-Mediated Protein Delivery In Vivo

et al. 2019

View full text Add to dashboard Cite

show abstract

“…25,27 GB models have been studied extensively in the context of protein design but also molecular dynamics, free energy simulations, acid/base calculations, ligand binding and protein folding. 25,[28][29][30][31][32] They reproduce the behavior of the dielectric continuum model rather accurately. Therefore, an energy function that combines molecular mechanics for the protein with a Generalized Born solvent can be considered "physics-based", even though it is not entirely constructed from first principles.…”

Section: Introductionmentioning

confidence: 93%

A physics-based energy function allows the computational redesign of a PDZ domain

Opuu

Sun

Hou

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

A powerful approach to understand protein structure and evolution is to perform computer simulations that mimic aspects of evolution. In particular, structure-based computational protein design (CPD) can address the inverse folding problem, exploring a large space of amino acid sequences and selecting ones predicted to adopt a given fold. Previously, CPD has been used to entirely redesign several proteins: all or most of the protein sequence was allowed to mutate freely; among sampled sequences, those with low computed folding energy were selected, and a few percent of them did indeed adopt the correct fold. Those studies used an energy function that was partly or largely knowledge-based, with several empirical terms. Here, we show that a PDZ domain can be entirely redesigned using a "physics-based" energy function that combines standard molecular mechanics and a recent, continuum electrostatic solvent model. Many thousands of sequences were generated by Monte Carlo simulation. Among the lowest-energy sequences, three were chosen for experimental testing. All three could be overexpressed and had native-like circular dichroism and 1D-NMR spectra. Two exhibited an increase in their thermal denaturation curves when a peptide ligand was present, indicating binding and suggesting correctly folded proteins. Evidently, the physical principles that govern molecular mechanics and continuum electrostatics are sufficient to perform whole-protein redesign. This is encouraging, since these methods provide physical insights, can be systematically improved, and are transferable to other biopolymers and ligands of medical or technological interest.2

show abstract

“…Computer simulations are a complementary tool, well suited to study solvated proteins, their structure, dynamics, and ligand binding (22)(23)(24)(25)(26). Of particular interest are nonempirical methods that predict binding free energy differences from molecular dynamics (MD) simulations without any adjustable parameters (27)(28)(29).…”

Section: Introductionmentioning

confidence: 99%

“…We mostly used the AMBER ff99SB additive force field (32,47). Six of the ff99SB alchemical mutations were reported earlier (26). For four of the ionic mutations, we also used the CHARMM C36 additive force field (33,48) and the CHARMM Drude polarizable force field (44)(45)(46).…”

Section: Introductionmentioning

confidence: 99%

Accurate PDZ/Peptide Binding Specificity with Additive and Polarizable Free Energy Simulations

Panel

Villa

Fuentes

et al. 2018

Biophysical Journal

Self Cite

View full text Add to dashboard Cite

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.

show abstract

A Simple PB/LIE Free Energy Function Accurately Predicts the Peptide Binding Specificity of the Tiam1 PDZ Domain

Cited by 11 publications

References 57 publications

Electrostatically Driven Guanidinium Interaction Domains that Control Hydrogel-Mediated Protein Delivery In Vivo

Electrostatically Driven Guanidinium Interaction Domains that Control Hydrogel-Mediated Protein Delivery In Vivo

A physics-based energy function allows the computational redesign of a PDZ domain

Accurate PDZ/Peptide Binding Specificity with Additive and Polarizable Free Energy Simulations

Contact Info

Product

Resources

About