A comprehensive and concrete exploration into the deactivation mechanisms of luminescent materials is imperative, with the improvement of simulating and computing technology. In this study, an integrated calculation scheme is employed on five Ir(III) complexes for thorough investigation of their photophysical properties, including radiative ( k) and nonradiative ( k) decay rates. As a most famous Ir(III) complex with superior quantum efficiency, fac-Ir(ppy) herein serves as a reference relative to the other four β-diketonate complexes. Both temperature-independent and temperature-dependent k are taken into account quantitatively for the first time, to unearth the role of different ancillary ligands in the determination of luminescent properties. Since the validated calculations of k for the five complexes are of the same order of magnitude, the nonemissive peculiarity of 4 is caused by large k. The newly designed compound 5, which simply has two more -CH groups than 4 in the ancillary ligand, further manifests that the reason for large k in molecule 4 should be attributed to the ligand resonance caused by great π conjugation.

Cytochrome P450 3A4 (CYP3A4) is the main P450 enzyme for drug metabolism and drug–drug interactions (DDIs), as it is involved in the metabolic process of approximately 50% of drugs. A detailed mechanistic elucidation of DDIs mediated by CYP3A4 is commonly believed to be critical for drug optimization and rational use. Here, two typical probes, midazolam (MDZ, substrate) and testosterone (TST, allosteric effector), are used to investigate the molecular mechanism of CYP3A4-mediated heterotropic allosteric interactions, through conventional molecular dynamics (cMD) and well-tempered metadynamics (WT-MTD) simulations. Distance monitoring shows that TST can stably bind in two potential peripheral sites (Site 1 and Site 2) of CYP3A4. The binding of TST at these two sites can induce conformational changes in CYP3A4 flexible loops on the basis of conformational analysis, thereby promoting the transition of the MDZ binding mode and affecting the ratio of MDZ metabolites. According to the results of the residue interaction network, multiple allosteric communication pathways are identified that can provide vivid and applicable insights into the heterotropic allostery of TST on MDZ metabolism. Comparing the regulatory effects and the communication pathways, the allosteric effect caused by TST binding in Site 2 seems to be more pronounced than in Site 1. Our findings could provide a deeper understanding of CYP3A4-mediated heterotropic allostery at the atomic level and would be helpful for rational drug use as well as the design of new allosteric modulators.

Protein–protein interaction plays an important role in the development of almost all cells. Elucidating the dynamic binding and affinity of a protein–protein complex is essential for understanding the biological functions of proteins. EphA6 and Odin proteins are members of the Eph (erythropoietin-producing hepatocyte) receptor family and the Anks (ankyrin repeat and sterile α motif domain-containing) family, respectively. Odin significantly functions in regulating endocytosis, degradation, and stability of EphA receptors. In this work, the key residues of the interaction interface were determined through a hydrogen bond, root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), and dynamic correlation analysis of the conventional molecular dynamics (MD) simulations. The calculated standard binding free energy, −7.92 kcal/mol, between EphA6 and Odin is quite consistent with the experimental measurement value, −8.73 kcal/mol. By the combination of several MD simulation techniques, our investigation of the binding process reveals the detailed representative characteristics of the entire binding pathway at the molecular level. Based on the obtained potential of the mean force (PMF) curve, the analysis of the simulation trajectories shows that the residue Arg1013 in the receptor EphA6 is responsible for capturing Asp739 and Asp740 in the ligand Odin during the initial stage of binding. In the later stage of binding, the hydrogen bonds and salt bridges between a series of residues Lys973, Leu1007, Gly1009, His1010, and Arg1012 in the receptor and residues Leu735, Asn736, Asp739, Asp740, and Asp753 in the ligand mainly contribute to the stability of the protein complex. In addition, the specific change process of the receptor–ligand-binding mode is also clarified during the binding process. Our present simulation will promote a deep understanding of the protein–protein interaction, and the identified key interresidue interaction will be theoretical guidance for the design of protein drugs.

The ongoing pandemic of COVID-19 caused by SARS-CoV-2 has become a global health problem. There is an urgent need to develop therapeutic drugs, effective therapies, and vaccines to prevent the spread of the virus. The virus first enters the host cell through the interaction between the receptor binding domain (RBD) of spike protein and the peptidase domain (PD) of the angiotensin-converting enzyme 2 (ACE2). Therefore, blocking the binding of RBD and ACE2 is a promising strategy to inhibit the invasion and infection of the virus in the host cell. In the study, we designed several miniprotein inhibitors against SARS-CoV-2 by single/double/triple-point mutant, based on the initial inhibitor LCB3. Molecular dynamics (MD) simulations and trajectory analysis were performed for an in-depth analysis of the structural stability, essential protein motions, and per-residue energy decomposition involved in the interaction of inhibitors with the RBD. The results showed that the inhibitors have adapted the protein RBD in the binding interface, thereby forming stable complexes. These inhibitors display low binding free energy in the MM/PBSA calculations, substantiating their strong interaction with RBD. Moreover, the binding affinity of the best miniprotein inhibitor, H6Y-M7L-L17F mutant, to RBD was ∼45 980 times (ΔG = RT ln K i ) higher than that of the initial inhibitor LCB3. Following H6Y-M7L-L17F mutant, the inhibitors with strong binding activity are successively H6Y-L17F, L17F, H6Y, and F30Y mutants. Our research proves that the miniprotein inhibitors can maintain their secondary structure and have a highly stable blocking (binding) effect on SARS-CoV-2. This study proposes novel miniprotein mutant inhibitors with enhanced binding to spike protein and provides potential guidance for the rational design of new SARS-CoV-2 spike protein inhibitors.

Two-dimensional (2D) boron carbide, carbon nitride, and silicon carbide are proposed with the aid of the density functional theory (DFT) simulations. These 2D systems are actually designed by doping the corresponding heteroatoms in the 2D Me-graphene (also called C568) system. Their structural stabilities are verified by analyzing their phonon relations. The mechanical strength of the Me-graphene-like silicon carbide (Me-C8Si4C) is weakened to some extent compared with the pristine Me-graphene, while the mechanical property of the proposed boron carbide (Me-C8B4C) is much enhanced. Moreover, according to our calculations at the HSE06 level, the Me-C8B4C system is metallic, while the proposed carbon nitride (Me-C8N4C) and silicon carbide (Me-C8Si4C) are semiconductors. Especially, the Me-C8N4C system exhibits a moderate band gap of 1.869 eV at the HSE06 level, which implies its application potentials in the solar conversion and photocatalysis fields. Furthermore, the influences of the biaxial strains on these designed systems are also discussed.