Measurement of the linewidth of a home-built vacuum ultraviolet comb by frequency comb spectroscopy on NO2.

Optical frequency comb in the vacuum ultraviolet (VUV)/extreme ultraviolet (XUV) region has attracted a great deal of attention, as it provides coherent VUV/XUV radiation source with a rather narrow bandwidth, facilitating precise spectroscopic measurements in the short wavelength regime. In this study, we report on the linewidth measurement of a home-built VUV comb centered at 148 nm using direct frequency comb spectroscopy with NO2. The measurement reveals that the upper bound of our comb linewidth is less than 28 MHz. Fitting the whole trace with different repetition rates shows that the center frequency of the excitation is 2 021.25 ± 0.24 THz (∼148.32 nm). Thus, we assigned this excitation to the transition from the 6a1 orbital (ν1'=0, ν2'=0) to the 3pσu orbital (ν1'=3, ν2'=8) in NO2. Our work demonstrates that VUV combs are potentially powerful tools for precision spectroscopic measurements in the short wavelength regime.

Drug-resistance mechanisms of three mutations in anaplastic lymphoma kinase against two inhibitors based on MM/PBSA combined with interaction entropy.

As a promising drug target in the treatment of lung cancer, anaplastic lymphoma kinase (ALK) and its mutations have been studied widely through the development of multiple generations of inhibitors. Experiments have found that compared with the wild-type, the L1198F and C1156Y/L1198F mutations resulted in resistance to 5P8 inhibitors, and the C1156Y mutation resulted in resistance to VGH inhibitors. In this study, the newly developed interaction entropy (IE) method combined with the polarized protein-specific charge (PPC) force field was utilized to explore the origin of the resistance mechanism of the ALK mutant system. The calculated binding free energy was consistent with the experimental results. Per-residue binding free energy decomposition showed that the predicted hot-spot residues (LEU1122, LEU/PHE1198, MET1199, GLY1202 and LEU1256) were almost identical across systems. Especially, the GLU1197 residue played an important role in inducing drug-resistance for both inhibitors. The electrostatic interaction of GLU1197, PHE1198 and MET1199 mainly resulted in the resistances of the L1198F and C1156Y/L1198F mutations to 5P8. And the van der Waals interaction energy of LEU1256 residue, and electrostatic energy and entropy change of GLU1197 resulted in the resistances of the C1156Y mutations to VGH. The indicated origins of the drug-resistance in the ALK systems provide a theoretical foundation for the design of potent inhibitors.

Binding Mechanism of Thrombin-Ligand Systems Investigated by a Polarized Protein-Specific Charge Force Field and Interaction Entropy Method.

In this study, 2 groups of 10 modified ligand systems with modified P3 and P2 side chains are used to study the binding mechanism with thrombin. Experimental results show that the binding affinity is enhanced by complex ligand side chains. The binding free energy obtained from the polarized protein-specific charge (PPC) force field combined with the newly developed interaction entropy (IE) method is consistent with the experimental values with a high correlation coefficient. On the contrary, poor correlation is obtained using the traditional normal mode (Nmode) method for calculating the entropy change. Furthermore, the binding free energy and hot-spot residue energy are decomposed, and the common hot-spot residues in the two groups of systems are Trp50, Leu96, Ile179, Asp199, Cyx201, Ser226, Trp227, Gly228, and Gly230. The electrostatic and van der Waals interaction energies were found to be the main contributors in the binding energy difference. CH-π and CH-CH interactions of Leu96 ligands are significantly related to the energy change due to the modified side chain, and the hydrogen bond between Asp199 and the ligand provides a strong electrostatic interaction, contributing to the binding free energy. Investigating the B-factor, principal component, and binding pocket also explains the change in the binding affinity caused by the modified side chains in ligands from the viewpoint of conformational change. This study demonstrates that the new IE method is superior to the Nmode method in the predicting binding free energy and emphasizes the importance of electronic polarization in molecular dynamics simulation. Moreover, from the viewpoint of energy and structure analysis, this study reveals the origin of the change in binding free energy in modified ligands with different binding sites.