Hierarchical graph learning for protein-protein interaction.

Protein-Protein Interactions (PPIs) are fundamental means of functions and signalings in biological systems. The massive growth in demand and cost associated with experimental PPI studies calls for computational tools for automated prediction and understanding of PPIs. Despite recent progress, in silico methods remain inadequate in modeling the natural PPI hierarchy. Here we present a double-viewed hierarchical graph learning model, HIGH-PPI, to predict PPIs and extrapolate the molecular details involved. In this model, we create a hierarchical graph, in which a node in the PPI network (top outside-of-protein view) is a protein graph (bottom inside-of-protein view). In the bottom view, a group of chemically relevant descriptors, instead of the protein sequences, are used to better capture the structure-function relationship of the protein. HIGH-PPI examines both outside-of-protein and inside-of-protein of the human interactome to establish a robust machine understanding of PPIs. This model demonstrates high accuracy and robustness in predicting PPIs. Moreover, HIGH-PPI can interpret the modes of action of PPIs by identifying important binding and catalytic sites precisely. Overall, "HIGH-PPI [ https://github.com/zqgao22/HIGH-PPI ]" is a domain-knowledge-driven and interpretable framework for PPI prediction studies.

Flavin catalyzed desulfurization of peptides and proteins in aqueous media.

A biomimetic method has been established for the chemo-selective desulfurization of cysteinyl peptides and proteins in aqueous media. The derivatives of biocatalytic cofactors, flavins, were found to be efficient photosensitizers in a thiyl-radical-mediated desulfurization of Cys. The reaction was conducted in an ultrafast manner with both polypeptides and proteins.

Chemo-Selective Cys-Pen Disulfide for Proximity-Induced Cysteine Cross-Linking.

Disulfide-rich architectures are valuable pharmacological tools or therapeutics. Besides, a ligand-induced conjugate strategy offers potential advantages in potency, selectivity, and duration of action for novel covalent drugs. Combining the plentiful disulfide-rich architecture library and ligand-induced conjugate via thiol-disulfide interchange would supply great benefits for developing site specific covalent inhibitors. Cysteine-cysteine (Cys-Cys) disulfide bonds are intrinsically unstable in endogenous reductive environment, while cysteine-penicillamine (Cys-Pen) disulfide bonds show satisfactory stability. We envisioned the Cys-Pen disulfide as a potential ligand-induced covalent bonding warhead, and this disulfide could reconstruct with the protein cysteine in the vicinity of the peptide binding site to form a new disulfide. To evaluate our design, protein PLCγ1-c src homology 2 domain and RGS3-PDZ domain were tested as models. Both proteins were successfully modified by Cys-Pen disulfide and formed new disulfides between proteins and peptides. The new disulfide was then analyzed to confirm it was a newly formed disulfide bond between Pen of the ligand and a protein Cys near the ligand binding site. HDAC4 was then chosen as a model by utilizing its "CXXC" domain near its catalytic pocket. The designed Cys-Pen cyclic peptide inhibitor of HDAC4 showed satisfactory selectivity and inhibitory effect.

Electrophilic Sulfonium-Promoted Peptide and Protein Amidation in Aqueous Media.

A novel amidation strategy using electrophilic sulfonium, which is soluble and stable in aqueous conditions, was developed. The sulfoniums could activate thioacid and carboxyl acid to efficiently react with amines to afford amides. This method enables applications in amidation in both aqueous media and solid-phase peptide synthesis, peptide/protein modifications, and reactive lysines of a proteome at pH 10 with activity-based protein profiling. A peptide ligand-directed labeling of the USP7-UBL2 domain was also performed using this method.

Organocatalytic silyl transfer from silylborane to nitroalkenes for the synthesis of ß-silyl nitroalkanes and ß-silyl amines.

The silylation of a wide array of nitroalkenes is achieved by organocatalysts in yields up to 93%. The reaction is carried out in a toluene/water biphasic solvent under operationally simple conditions. Reduction of the nitro group provides efficient access to functionalized ß-silyl amines.

Rhodium-Catalyzed Intramolecular C-H Silylation by Silacyclobutanes.

Silacyclobutane was discovered to be an efficient C-H bond silylation reagent. Under the catalysis of Rh(I) /TMS-segphos, silacyclobutane undergoes sequential C-Si/C-H bond activations, affording a series of π-conjugated siloles in high yields and regioselectivities. The catalytic cycle was proposed to involve a rarely documented endocyclic ß-hydride elimination of five-membered metallacycles, which after reductive elimination gave rise to a Si-Rh(I) species that is capable of C-H activation.

Rh(I)-Catalyzed Insertion of Allenes into C-C Bonds of Benzocyclobutenols.

Herein we report a Rh(I)-catalyzed two carbon insertion into C-C bonds of benzocyclobutenols by employing symmetrical and unsymmetrical allenes. This reaction provides rapid access to alkylidene tetralins bearing two adjacent stereogenic centers in good yields and diasteroselectivities.