We report new potential energy surfaces for six coupled 5A′ states and 14 3A′ of O3. The are created by parametrically managed diabatization deep neural network (PM-DDNN). PM-DDNN method uses calculated adiabatic to discover fit an underlying adiabatic-equivalent set diabatic their couplings obtains the diagonalization matrix (DPEM). procedure yields gradients, as well DPEM its gradient. If desired one can also compute nonadiabatic coupling due transformation. present work improves on...

Machine-learned representations of potential energy surfaces generated in the output layer a feedforward neural network are becoming increasingly popular. One difficulty with is that it often unreliable regions where training data missing or sparse. Human-designed potentials build proper extrapolation behavior by choice functional form. Because machine learning very efficient, desirable to learn how add human intelligence machine-learned convenient way. example well-understood feature...

Dynamics simulations of high-energy O2-O collisions play an important role in simulating thermal energy content and heat flux flows around hypersonic vehicles. To carry out such dynamics efficiently requires accurate global potential surfaces (in most algorithms) state couplings for many energetically accessible electronic states. The ability to treat involving coupled states has been a challenge decades. Very recently, new diabatization method, the parametrically managed by deep neural...

Theoretical investigation of the effect chirality on inhibitors is providing essential insights for drug design.

Although the quality of current additive all-atom force fields for carbohydrates has been demonstrated in many applications, occasional significant differences reported hydrodynamic behavior specific polysaccharides modeled with different is a cause concern. In particular, irreversible conformational collapse noted some polysaccharide simulations GLYCAM06j field. Here, we investigate this phenomenon through comparative range saccharides both and CHARMM36 carbohydrate fields. We find that...

Stability of the π–π stacking interactions in ben∥substituted-ben and ben∥substituted-COT complexes was studied using computational quantum chemistry methods (where ben COT are benzene cyclooctatetraene, ∥ denotes interaction, substituted-ben substituted-COT cyclooctatetraene which substituted with four ethynyl-X groups, respectively, X = OH, CH3, H, F, CF3, CN NO2). In these electron-withdrawing substituents lead to larger binding energies electron-donating ones weaker compared H. There...

A persistent challenge in the treatment of non-small cell lung cancer (NSCLC) with EGFR is emergence drug-resistant caused by somatic mutations. The L858R/T790 M double mutant (EGFRDM ) was found to be most alarming variant. Despite development a wide range inhibitors, none them could inhibit EGFRDM effectively. Recently, 11h and 45a, have been potent inhibitors against through two distinctive mechanisms, non-covalent covalent binding, respectively. However, structural dynamic implications...

Fluorination has considerable potential with regard to the design of kinase inhibitors for anticarcinoma therapy. It was recently reported that fluorination increases potency epidermal growth factor receptor (EGFR), mutations which have been linked specifically nonsmall-cell lung cancer. For L858R/T790M/C797S triplet mutant (EGFRTM), a difluorinated inhibitor, 25g, found 4.23 times greater against EGFRTM than an unfluorinated 25a. This discovery necessitates rational explanation underlying...

Abstract Spider silks have outstanding potential as biomaterials due to their sought‐after mechanical properties and low immunogenicity. The toughest spider silk is aciniform silk, which used by spiders wrap prey produce egg sacs. A variety of recombinant constructs are now been developed, including hybrid with domains from multiple proteins fused together. In this study, an engineered construct, termed N B Silk, both N‐ C‐terminally heptapeptide motifs that bind the neurotrophic factor...

Abstract 11h is a very potent inhibitor against epidermal growth factor receptor triple mutation L858R/T790M/C797S ( EGFR TM ) with 13‐fold stronger potency than the FDA ‐approved osimertinib. Recently, two new inhibitors, 11d and 11e , were reported which revealed 2.8‐ 2.3‐fold respectively. 11d, have same structures but differ only in their aliphatic chain length. However, exact effects of differential length on inhibitory potencies these compounds require further elaboration at atomistic...

Covalent modification of the oncogenic mutant epidermal growth factor receptor (EGFR) by small molecules is an efficient strategy for achieving enhanced and sustained pharmacological effect in treatment non-small-cell lung cancer. NSP-037 (18), irreversible inhibitor L858R/T790M double-mutant EGFR (EGFRDM) using α-chlorofluoroacetamide (CFA) as a novel warhead, has seven times inhibition selectivity EGFRDM over wild type (EGFRWT), compared to clinically approved osimertinib (7). Here, we...

Machine-learned representations of potential energy surfaces generated in the output layer a feedforward neural network are becoming increasingly popular. One difficulty with neural-network is that it often unreliable regions where training data missing or sparse. Human-designed potentials build proper extrapolation behavior by choice functional form. Because machine learning very efficient, desirable to learn how add human intelligence machine-learned convenient way. example well understood...

Abstract Secondary active membrane transporters harness the energy of ion gradients to concentrate their substrates. Homologous evolved couple transport different ions in response changing environments and needs. The bases such diversification, thus principles coupling, are unexplored. Employing phylogenetics ancestral protein reconstruction, we investigated sodium-coupled prokaryotic glutamate transporters, a mechanism ubiquitous across life domains critical neurotransmitter recycling...

The concept of chirality has become prominent over the years, particularly with regards to design therapeutic molecules. This phenomenon was recently reported for pro-carcinogenic fibroblast growth factor receptor 1 (FGFR1), wherein two inhibitors exhibited disparate inhibitory potencies due effects chirality. Therefore, ability R-enantiomer (R-21c) possess a potency 10.44 times that S-enantiomer (S-21c) leaves us curiosity investigate underlying mechanisms using computational methods....

Covalent targeting is a promising strategy for increasing the potency and selectivity of potential drug candidates. This therapeutic approach was recently reported epidermal growth factor receptor (EGFR), wherein covalent binder, 20g [N-(3-{7-[2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino]-3,4-dihydro-3-isopropyl-2,4-dioxopyrimido[4,5-d]pyrimidin-1(2H)-yl}phenyl)acrylamide], demonstrated significant inhibitory activity toward EGFR L858R/T790M double mutant (EGFRDM) relative to wild-type...

Abstract Spider silks are renowned for their mechanical properties. The notably tough Argiope trifasciata aciniform silk is spun from a protein predominantly comprising series of identical 200 residue units (“W units”). In solution, each W unit has globular 5‐helix domain connected to its neighbors by intrinsically disordered linkers while the fiber contains mixed α‐helical, β‐sheet and structuring. Helix 5 more dynamic prone denaturation than remainder domain, implying that it may...

Chirality in drug design has been attracting wide interests and attention over the years based on its innate potentials of enhancing selectivity prowess therapeutic molecules. This approach was fundamental to recent two inhibitors, where (R,R)-HEC72702 exhibited higher potency inhibition against hepatitis B virus capsid (HBVC) than (R,S)-HEC72702. Nevertheless, detailed molecular mechanism remained unresolved. Here, we apply multiple computational approaches explore, validate, differentiate...

The phosphatidylinostitol-3-kinase (PI3K)/AKT/mammalian target of rapamycin signaling pathway is a vital regulator cell proliferation, growth, and survival, which frequently overactivated in many human cancers. To this effect, PI3K, an important mediator pathway, has been pinpointed as crucial cancer therapy hence the importance PI3K inhibitors. It was recently reported that defluorination pyridine-to-pyrimidine ring interconversion increase potency specific small-molecule inhibitors PI3K....