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1. De novo design of a stapled peptide targeting SARS-CoV-2 spike protein receptor-binding domain

   https://doi.org/10.5281/zenodo.7844171  

   Thakkar, Ravindra; Comer, Jeffrey (April 2023, RSC medicinal chemistry)

   The dataset provided for the manuscript entitled "De novo design of a stapled peptide targeting SARS-CoV-2 spike protein receptor-binding domain" encompasses all the required files to execute and analyze simulations of a designed stapled peptide (Pep 39) attached to spike protein receptor binding domain in the most stable binding configuration, illustrated in Figure 3 of the paper. The dataset is composed of molecular model structure files in NAMD psf format, force field parameter files in CHARMM format, initial atomic coordinates in PDB format, NAMD configuration files, NAMD output files (which consist of restart files in binary NAMD format), and trajectories in dcd format (downsampled to 10 ns per frame). To manage the analysis, there are shell scripts (that work with Bash) that invoke VMD Tcl scripts. These scripts and their output are also contained in the dataset. 

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2. A Paired Database of Predicted and Experimental Protein Peptide Binding Information

   https://doi.org/10.1038/s41597-025-05754-7  

   Torres, Jazmine A; Kieslich, Chris A; Pantazes, Robert J (December 2025, Scientific Data)

   Abstract Peptides are important biomolecules, and their interactions with proteins make them useful in sensing and therapeutic applications. Computational peptide design methods can benefit from high-quality peptide-protein structures paired with thermodynamic data. The Predicted and Experimental Peptide Binding Information (PEPBI) database provides 329 predicted peptide-protein complexes, each based on an experimentally determined structure, with corresponding experimental measurements of changes in Gibbs free energy, enthalpy, and entropy. For each complex, 40 properties calculated using Rosetta’s Interface Analyzer are included. Complexes were selected for inclusion in PEPBI using eight stringent structural criteria, including peptide length (5–20 residues), structure resolution (≤2.0 Å), less than 30% sequence identity between complexes, and having a corresponding unbound protein structure in the Protein Data Bank with at least 90% sequence identity to the bound form with minimal changes in the binding pocket. PEPBI is expected to be of use for the development of computational methods for peptide design with desired binding properties to protein targets. 

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3. Metal-Promoted Higher-Order Assembly of Disulfide-Stapled Helical Barrels

   https://doi.org/10.3390/nano13192645  

   Agrahari, Ashutosh; Lipton, Mark; Chmielewski, Jean (October 2023, Nanomaterials)

   Peptide-based helical barrels are a noteworthy building block for hierarchical assembly, with a hydrophobic cavity that can serve as a host for cargo. In this study, disulfide-stapled helical barrels were synthesized containing ligands for metal ions on the hydrophilic face of each amphiphilic peptide helix. The major product of the disulfide-stapling reaction was found to be composed of five amphiphilic peptides, thereby going from a 16-amino-acid peptide to a stapled 80-residue protein in one step. The structure of this pentamer, 5HB1, was optimized in silico, indicating a significant hydrophobic cavity of ~6 Å within a helical barrel. Metal-ion-promoted assembly of the helical barrel building blocks generated higher order assemblies with a three-dimensional (3D) matrix morphology. The matrix was decorated with hydrophobic dyes and His-tagged proteins both before and after assembly, taking advantage of the hydrophobic pocket within the helical barrels and coordination sites within the metal ion-peptide framework. As such, this peptide-based biomaterial has potential for a number of biotechnology applications, including supplying small molecule and protein growth factors during cell and tissue growth within the matrix. 

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4. Structure-based discovery of hydrocarbon-stapled paxillin peptides that block FAK scaffolding in cancer

   https://doi.org/10.1038/s41467-025-57196-9  

   Reyes, Lauren; Naser, Lena; Weiner, Warren S; Thifault, Darren; Stahl, Erik; McCreary, Liam; Nott, Rohini; Quick, Colton; Buchberger, Alex; Alvarado, Carlos; et al (December 2025, Nature Communications)

   The focal adhesion kinase (FAK) scaffold provides FAK-targeted cancer therapeutics with greater efficacy and specificity than traditional kinase inhibitors. The FAK scaffold function largely involves the interaction between FAK’s focal adhesion targeting (FAT) domain and paxillin, ultimately regulating many hallmarks of cancer. We report the design of paxillin LD-motif mimetics that successfully inhibit the FAT-paxillin interaction. Chemical and biochemical screening identifies stapled peptide 1907, a high affinity binder of the FAT four-helix bundle with ~100-fold greater binding affinity than the native LD2-sequence. The X-ray co-crystal structure of the FAT-1907 complex is solved. Myristoylated 1907-analog, peptide 2012, delocalizes FAK from focal adhesions, induces cancer cell apoptosis, reduces in vitro viability and invasion, and decreases tumor burden in B16F10 melanoma female mice. Enzymatic FAK inhibition produces no comparable effects. Herein, we describe a biologically potent therapeutic strategy to target the FAK-paxillin complex, a previously deemed undruggable protein-protein interaction. 

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5. Engineering gain‐of‐function mutants of a WW domain by dynamics and structural analysis

   https://doi.org/10.1002/pro.4759  

   Lu, Jin; Rahman, Mohammad Imtiazur; Kazan, I. Can; Halloran, Nicholas R.; Bobkov, Andrey A.; Ozkan, S. Banu; Ghirlanda, Giovanna (September 2023, Protein Science)

   Proteins gain optimal fitness such as foldability and function through evolutionary selection. However, classical studies have found that evolutionarily designed protein sequences alone cannot guarantee foldability, or at least not without considering local contacts associated with the initial folding steps. We previously showed that foldability and function can be restored by removing frustration in the folding energy landscape of a model WW domain protein, CC16, which was designed based on Statistical Coupling Analysis (SCA). Substitutions ensuring the formation of five local contacts identified as “on‐path” were selected using the closest homolog native folded sequence, N21. Surprisingly, the resulting sequence, CC16‐N21, bound to Group I peptides, while N21 did not. Here, we identified single‐point mutations that enable N21 to bind a Group I peptide ligand through structure and dynamic‐based computational design. Comparison of the docked position of the CC16‐N21/ligand complex with the N21 structure showed that residues at positions 9 and 19 are important for peptide binding, whereas the dynamic profiles identified position 10 as allosterically coupled to the binding site and exhibiting different dynamics between N21 and CC16‐N21. We found that swapping these positions in N21 with matched residues from CC16‐N21 recovers nature‐like binding affinity to N21. This study validates the use of dynamic profiles as guiding principles for affecting the binding affinity of small proteins. 

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