Ab initio calculations are performed to elucidate the mechanism of the photoisomerization of azobenzene. We obtain the excitation energies of the S1(n→π*), S2(π→π*), and S3(n2→π*2) states by complete active space self-consistent field (CASSCF) and multireference single double configuration interaction (MRSDCI) calculations. Two-dimensional potential surfaces of the ground- and excited states are obtained at the CASSCF level in order to investigate the isomerization pathways. A conical intersection between the ground state and the S1 state is found near the midpoint of the rotation pathway, and causes a radiationless transition. On the other hand, the S2 state has local minima at the cis and trans structures, so that the isomerization proceeds at the S2 surface following the deexcitation.

Background Alectinib has shown a greater efficacy to ALK -rearranged non-small-cell lung cancers in first-line setting; however, most patients relapse due to acquired resistance, such as secondary mutations in ALK including I1171N and G1202R. Although ceritinib or lorlatinib was shown to be effective to these resistant mutants, further resistance often emerges due to ALK-compound mutations in relapse patients following the use of ceritinib or lorlatinib. However, the drug for overcoming resistance has not been established yet. Methods We established lorlatinib-resistant cells harboring ALK-I1171N or -G1202R compound mutations by performing ENU mutagenesis screening or using an in vivo mouse model. We performed drug screening to overcome the lorlatinib-resistant ALK-compound mutations. To evaluate these resistances in silico , we developed a modified computational molecular dynamic simulation (MP-CAFEE). Findings We identified 14 lorlatinib-resistant ALK-compound mutants, including several mutants that were recently discovered in lorlatinib-resistant patients. Some of these compound mutants were found to be sensitive to early generation ALK-TKIs and several BCR-ABL inhibitors. Using our original computational simulation, we succeeded in demonstrating a clear linear correlation between binding free energy and in vitro experimental IC 50 value of several ALK-TKIs to single- or compound-mutated EML4-ALK expressing Ba/F3 cells and in recapitulating the tendency of the binding affinity reduction by double mutations found in this study. Computational simulation revealed that ALK-L1256F single mutant conferred resistance to lorlatinib but increased the sensitivity to alectinib. Interpretation We discovered lorlatinib-resistant multiple ALK-compound mutations and an L1256F single mutation as well as the potential therapeutic strategies for these ALK mutations. Our original computational simulation to calculate the binding affinity may be applicable for predicting resistant mutations and for overcoming drug resistance in silico. Fund This work was mainly supported by MEXT/JSPS KAKENHI Grants and AMED Grants.

We performed fragment molecular orbital (FMO) calculations to examine the molecular interactions between the prion protein (PrP) and GN8, which is a potential curative agent for prion diseases. This study has the following novel aspects: we introduced the counterpoise method into the FMO scheme to eliminate the basis set superposition error and examined the influence of geometrical fluctuation on the interaction energies, thereby enabling rigorous analysis of the molecular interaction between PrP and GN8. This analysis could provide information on key amino acid residues of PrP as well as key units of GN8 involved in the molecular interaction between the two molecules. The present FMO calculations were performed using an original program developed in our laboratory, called "Parallelized ab initio calculation system based on FMO (PAICS)".

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