In silico screening of protein-binding peptides with an application to developing peptide inhibitors against antibiotic resistance.

The field of therapeutic peptides is experiencing a surge, fueled by their advantageous features. These include predictable metabolism, enhanced safety profile, high selectivity, and reduced off-target effects compared with small-molecule drugs. Despite progress in addressing limitations associated with peptide drugs, a significant bottleneck remains: the absence of a large-scale in silico screening method for a given protein target structure.

The role of METTL3-mediated CircStk4 modification in the treatment of chronic glomerulonephritis with Qi Teng Xiao Zhuo granule.

Background: Qi Teng Xiao Zhuo granule (QTXZG), a compound preparation used in traditional Chinese medicine, is a highly effective treatment for chronic glomerulonephritis (CGN). Previously, the mechanism of circStk4 and the N-methyladenosine (mA) modification of circStk4 in CGN was elucidated in vivo. Nevertheless, there hasn't been any research done on the connection between circStk4 and QTXZG's mechanism in CGN treatment.

Exploring the mechanism of Corbrin capsules in the intervention of AKI-COVID-19 based on network pharmacology combined with GEO dataset.

Aim: of the study: This study used network pharmacology and the Gene Expression Omnibus (GEO) database to investigate the therapeutic effects of Corbrin capsules on acute kidney injury (AKI)-COVID-19 (coronavirus disease 2019).

Materials And Methods: The active constituents and specific molecular targets of Corbrin capsules were obtained from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) and Swiss Target Prediction databases. The targets related to AKI and COVID-19 disease were obtained from the Online Mendelian Inheritance in Man (OMIM), GeneCards, and GEO databases.

Impact of AlphaFold on structure prediction of protein complexes: The CASP15-CAPRI experiment.

We present the results for CAPRI Round 54, the 5th joint CASP-CAPRI protein assembly prediction challenge. The Round offered 37 targets, including 14 homodimers, 3 homo-trimers, 13 heterodimers including 3 antibody-antigen complexes, and 7 large assemblies. On average ~70 CASP and CAPRI predictor groups, including more than 20 automatics servers, submitted models for each target.

Current Computational Methods for Protein-peptide Complex Structure Prediction.

Peptide-mediated protein-protein interactions (PPIs) play an important role in various biological processes. The development of peptide-based drugs to modulate PPIs has attracted increasing attention due to the advantages of high specificity and low toxicity. In the development of peptide-based drugs, one of the most important steps is to determine the interaction details between the peptide and the target protein.

Identification of Rab7 as an autophagy marker: potential therapeutic approaches and the effect of Qi Teng Xiao Zhuo granule in chronic glomerulonephritis.

Context: Qi Teng Xiao Zhuo granule (QTXZG) is a traditional Chinese medicine (TCM) used for therapeutic effects on chronic glomerulonephritis (CGN). However, the underlying mechanism remains unclear.

Objective: To investigate the molecular mechanism of QTXZG on CGN by proteomics.

Discriminating physiological from non-physiological interfaces in structures of protein complexes: A community-wide study.

Reliably scoring and ranking candidate models of protein complexes and assigning their oligomeric state from the structure of the crystal lattice represent outstanding challenges. A community-wide effort was launched to tackle these challenges. The latest resources on protein complexes and interfaces were exploited to derive a benchmark dataset consisting of 1677 homodimer protein crystal structures, including a balanced mix of physiological and non-physiological complexes.

Template-guided method for protein-ligand complex structure prediction: Application to CASP15 protein-ligand studies.

Critical Assessment of Structure Prediction 15 (CASP15) added a new category of ligand prediction to promote the development of protein/RNA-ligand modeling methods, which have become important tools in modern drug discovery. A total of 22 targets were released, including 18 protein-ligand targets and 4 RNA-ligand targets. We applied our recently developed template-guided method to the protein-ligand complex structure predictions.

An allosteric modulator activates BK channels by perturbing coupling between Ca binding and pore opening.

BK type Ca-activated K channels activate in response to both voltage and Ca. The membrane-spanning voltage sensor domain (VSD) activation and Ca binding to the cytosolic tail domain (CTD) open the pore across the membrane, but the mechanisms that couple VSD activation and Ca binding to pore opening  are not clear. Here we show that a compound, BC5, identified from in silico screening, interacts with the CTD-VSD interface and specifically modulates the Ca dependent activation mechanism.

Predicting Protein-Peptide Complex Structures by Accounting for Peptide Flexibility and the Physicochemical Environment.

Predicting protein-peptide complex structures is crucial to the understanding of a vast variety of peptide-mediated cellular processes and to peptide-based drug development. Peptide flexibility and binding mode ranking are the two major challenges for protein-peptide complex structure prediction. Peptides are highly flexible molecules, and therefore, brute-force modeling of peptide conformations of interest in protein-peptide docking is beyond current computing power.

Dissimilar Ligands Bind in a Similar Fashion: A Guide to Ligand Binding-Mode Prediction with Application to CELPP Studies.

The molecular similarity principle has achieved great successes in the field of drug design/discovery. Existing studies have focused on similar ligands, while the behaviors of dissimilar ligands remain unknown. In this study, we developed an intercomparison strategy in order to compare the binding modes of ligands with different molecular structures.

A Selective Tether Recruits Activated Response Regulator CheB to Its Chemoreceptor Substrate.

Methylesterase/deamidase CheB is a key component of bacterial chemotaxis systems. It is also a prominent example of a two-component response regulator in which the effector domain is an enzyme. Like other response regulators, CheB is activated by phosphorylation of an aspartyl residue in its regulatory domain, creating an open conformation between its two domains.

Prediction of protein assemblies, the next frontier: The CASP14-CAPRI experiment.

We present the results for CAPRI Round 50, the fourth joint CASP-CAPRI protein assembly prediction challenge. The Round comprised a total of twelve targets, including six dimers, three trimers, and three higher-order oligomers. Four of these were easy targets, for which good structural templates were available either for the full assembly, or for the main interfaces (of the higher-order oligomers).

Modulating the voltage sensor of a cardiac potassium channel shows antiarrhythmic effects.

Cardiac arrhythmias are the most common cause of sudden cardiac death worldwide. Lengthening the ventricular action potential duration (APD), either congenitally or via pathologic or pharmacologic means, predisposes to a life-threatening ventricular arrhythmia, Torsade de Pointes. I (KCNQ1+KCNE1), a slowly activating K current, plays a role in action potential repolarization.

A PIP substitute mediates voltage sensor-pore coupling in KCNQ activation.

KCNQ family K channels (KCNQ1-5) in the heart, nerve, epithelium and ear require phosphatidylinositol 4,5-bisphosphate (PIP) for voltage dependent activation. While membrane lipids are known to regulate voltage sensor domain (VSD) activation and pore opening in voltage dependent gating, PIP was found to interact with KCNQ1 and mediate VSD-pore coupling. Here, we show that a compound CP1, identified in silico based on the structures of both KCNQ1 and PIP, can substitute for PIP to mediate VSD-pore coupling.

MDockPeP: A Web Server for Blind Prediction of Protein-Peptide Complex Structures.

Protein-peptide interactions mediate a wide range of important cellular tasks. In silico prediction of protein-peptide complex structure is highly desirable for mechanistic investigation of these processes and for therapeutic design. Recently, we developed a docking-based method for predicting protein-peptide complex structures, which starts with the peptide sequence and globally docks the all-atom, flexible peptide onto the protein structure.

Performance of human and server prediction in CAPRI rounds 38-45.

CAPRI challenges offer a variety of blind tests for protein-protein interaction prediction. In CAPRI Rounds 38-45, we generated a set of putative binding modes for each target with an FFT-based docking algorithm, and then scored and ranked these binding modes with a proprietary scoring function, ITScorePP. We have also developed a novel web server, Rebipp.

Two-stage electro-mechanical coupling of a K channel in voltage-dependent activation.

In voltage-gated potassium (K) channels, the voltage-sensing domain (VSD) undergoes sequential activation from the resting state to the intermediate state and activated state to trigger pore opening via electro-mechanical (E-M) coupling. However, the spatial and temporal details underlying E-M coupling remain elusive. Here, utilizing K7.

PepPro: A Nonredundant Structure Data Set for Benchmarking Peptide-Protein Computational Docking.

We present a nonredundant benchmark, coined PepPro, for testing peptide-protein docking algorithms. Currently, PepPro contains 89 nonredundant experimentally determined peptide-protein complex structures, with peptide sequence lengths ranging from 5 to 30 amino acids. The benchmark covers peptides with distinct secondary structures, including helix, partial helix, a mixture of helix and β-sheet, β-sheet formed through binding, β-sheet formed through self-folding, and coil.

Blind prediction of homo- and hetero-protein complexes: The CASP13-CAPRI experiment.

We present the results for CAPRI Round 46, the third joint CASP-CAPRI protein assembly prediction challenge. The Round comprised a total of 20 targets including 14 homo-oligomers and 6 heterocomplexes. Eight of the homo-oligomer targets and one heterodimer comprised proteins that could be readily modeled using templates from the Protein Data Bank, often available for the full assembly.

Predicting protein-ligand binding modes for CELPP and GC3: workflows and insight.

Drug Design Data Resource (D3R) continues to release valuable benchmarking datasets to promote improvement and development of computational methods for new drug discovery. We have developed several methods for protein-ligand binding mode prediction during the participation in the D3R challenges. In the present study, these methods were integrated, automated, and systematically tested using the large-scale data from Continuous Evaluation of Ligand Pose Prediction (CELPP) and a subset of Grand challenge 3 (GC3).

LncRNAs expression in adriamycin-induced rats reveals the potential role of LncRNAs contributing to chronic glomerulonephritis pathogenesis.

Background: Chronic glomerulonephritis (CGN) is the most common form of primary glomerular disease with unclear molecular mechanisms. Currently, limited study on long non-coding RNAs (lncRNAs) in CGN is available. Our study aimed to identify potential lncRNAs and genes in the normal and adriamycin-induced CGN rats, which to explore the potential molecular mechanisms of CGN pathogenesis.