Discovery of potential RIPK1 inhibitors by machine learning and molecular dynamics simulations.

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) plays a crucial role in inflammation and cell death, so it is a promising candidate for the treatment of autoimmune, inflammatory, neurodegenerative, and ischemic diseases. So far, there are no approved RIPK1 inhibitors available. In this study, four machine learning algorithms were employed (random forest, extra trees, extreme gradient boosting and light gradient boosting machine) to predict small molecule inhibitors of RIPK1. The statistical metrics revealed similar performance and demonstrated outstanding predictive capabilities in all four models. Molecular docking and clustering analysis were employed to confirm six compounds that are structurally distinct from existing RIPK1 inhibitors. Subsequent molecular dynamics simulations were performed to evaluate the binding ability of these compounds. Utilizing the Shapley additive explanation (SHAP) method, the 1855 bit has been identified as the most significant molecular fingerprint fragment. The findings propose that these six small molecules exhibit promising potential for targeting RIPK1 in associated diseases. Notably, the identification of Cpd-1 small molecule (ZINC000085897746) from the Musa acuminate highlights its natural product origin, warranting further attention and investigation.

Molecular simulations study of novel 1,4-dihydropyridines derivatives with a high selectivity for Cav3.1 calcium channel.

1,4-Dihydropyridines (DHPs) have been developed to treat hypertension, angina, and nerve system disease. They are thought to mainly target the L-type calcium channels, but low selectivity prompts them to block Cav1.2 and Cav3.1 channels simultaneously. Recently, some novel DHPs with different hydrophobic groups have been synthesized and among them M12 has a higher selectivity for Cav3.1. However, the structural information about Cav3.1-DHPs complexes is not available in the experiment. Thus, we combined homology modeling, molecular docking, molecular dynamics simulations, and binding free energy calculations to quantitatively elucidate the inhibition mechanism of DHPs. The calculated results indicate that our model is in excellent agreement with experimental results. On the basis of conformational analysis, we identify the main interactions between DHPs and calcium channels and further elaborate on the different selectivity of ligands from the micro perspective. In conjunction with energy distribution, we propose that the binding sites of Cav3.1-DHPs is characterized by several interspersed hydrophobic amino acid residues on the IIIS6 and IVS6 segments. We also speculate the favorable function groups on prospective DHPs. Besides, our model provides important information for further mutagenesis experiments.

Understanding the Effects of Bidentate Directing Groups: A Unified Rationale for sp(2) and sp(3) C-H Bond Activations.

Bidentate directing group (DG) strategy is a promising way to achieve sp(2) and more inert sp(3) C-H bond activations in transition metal (TM) catalysis. In this work, we systematically explored the assisting effects exerted by bidentate DGs in the C-H bond activations. Through DFT calculations and well-defined comparative analysis, we for the first time unified the rationale of the reactivity promoted by bidentate DG in sp(2) and sp(3) C-H activations, which are generally consistent with available experimental discoveries about the C-H activation reactivity up to date. In addition to the general rationale of the reactivity, the assisting effects of several typical bidentate DGs were also quantitatively evaluated and compared to reveal their relative promoting ability for C-H activation reactivity. Finally, the effect of the ligating group charge and the position of the ligating group charge in bidentate DGs were also investigated, based on which new types of DGs were designed and proposed to be potentially effective in C-H activation. The deeper understanding and new insight about the bidentate DG strategy gained in this work would help to enhance its further experimental development in sp(2) and sp(3) C-H bond activations.

Direct ab initio study on the rate constants of radical C2(A 3Π(u)) + C3H8 reaction.

The mechanism and kinetics of the radical (3)C(2) + C(3)H(8) reaction have been investigated theoretically by direct ab initio kinetics over a wide temperature range. The potential energy surfaces have been constructed at the CCSD(T)/B3//UMP2/B1 levels of theory. The electron transfer was also analyzed by quasi-restricted orbital (QRO) in detail. It was shown that all these channels proceed exclusively via hydrogen abstraction. The overall ICVT/SCT rate constants are in agreement with the available experimental results. The prediction shows that the secondary hydrogen of C(3)H(8) abstraction by (3)C(2) radical is the major pathway at low temperatures (below 700 K), while as the temperature increases, the primary hydrogen of C(3)H(8) abstraction becomes more important and more favorable. A negative temperature dependence of the rate constants for the reaction of (3)C(2) + C(3)H(8) was observed. The three-(k (3)) and four-parameter (k (4)) rate-temperature expressions were also provided within 243-2000 K to facilitate future experimental studies.

Molecular dynamics simulations of the thermal stability of tteRBP and ecRBP.

Molecular dynamics simulations were performed for investigating the thermal stability of the extremely thermophilic Thermoanaerobacter tengcongensis ribose binding protein (tteRBP) and the mesophilic homologous Escherichia coli ribose binding protein (ecRBP). The simulations for the two proteins were carried out under the room temperature (300 K) and the optimal activity temperature (tteRBP 375 K and ecRBP 329 K), respectively. The comparative analyses of the trajectories show that the two proteins have stable overall structures at the two temperatures; further analyses indicate that they both have strong side-chain interactions and different backbone flexibilities at the different temperatures. The tteRBP 375 K and ecRBP 329 K have stronger internal motion and higher flexibility than tteRBP 300 K and ecRBP 300 K, respectively, it is noted that the flexibility of tteRBP is much higher than that of ecRBP at the two temperatures. Therefore, tteRBP 375 K can adapt to high temperature due to its higher flexibility of backbone. Combining with the researches by Cuneo et al., it is concluded that the side-chain interactions and flexibility of backbone are both the key factors to maintain thermal stability of the two proteins. An animated Interactive 3D Complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:22.

Molecular simulations study of ligand-release mechanism in an odorant-binding protein from the southern house mosquito.

Pheromone-binding proteins transport hydrophobic pheromones through the aqueous medium to their receptors. The odorant-binding protein (OBP) of Culex quinquefasciatus (CquiOBP1), which binds to an oviposition pheromone (5R,6S)-6-acetoxy-5-hexadecanolide (MOP), plays a key role in sensing oviposition cues. However, so far the mechanism of MOP release from the protein is unclear. Therefore, in this contribution the process and pathway of the MOP release from CquiOBP1 are determined by conventional molecular dynamics, essential dynamics (ED), and ED sampling. The detailed analysis of the release process suggests the intrinsic flexibility of MOP, the distribution of contacts with MOP and local conformational changes of CquiOBP1 is crucial.

Comparison of the FeO(2+) and FeS(2+) complexes in the cyanide and isocyanide ligand environment for methane hydroxylation.

A general comparison of fundamental distinctions between the FeO(2+) and FeS(2+) complexes in an identical cyanide or isocyanide ligand environment for methane hydroxylation has been probed computationally in this work in a series of hypothetical [Fe(IV)(X)(CN)5](3-), [Fe(IV)(X)(NC)5](3-), (X = O, S) complexes. We have detailed an analysis of the geometric and electronic structures using density functional theory calculations. In addition, their σ- and π-mechanisms in C-H bond activation process have been described with the aid of the schematic molecular orbital diagram. From our theoretical results, it is shown that (a) the iron(IV)-sulfido complex apparently is able to hydroxylate C-H bond of methane as good as the iron(IV)-oxo species, (b) the O-CN, S-CN complexes have an inherent preference for the low-spin state, while for the case of O-NC and S-NC in which S = 1 and S = 2 states are relatively close in energy, (c) each of the d block electron orbital plays an important role, which is not just spectator electron, and (d) in comparison to the cyanide and isocyanide ligand environment, we can see that the FeS(2+) species prefer the cyanide ligand environment, while the FeO(2+) species favor the isocyanide ligand environment. In addition, a remarkably good correlation of the σ-/π-mechanism for hydrogen abstraction from methane with the gap between the Fe-dz2 (α) and C-H (α) pair as well as the Fe-dxz/yz (ß) and C-H (ß) pair has been found.

Mechanism insights of ethane C-H bond activations by bare [Fe(III)═O]+: explicit electronic structure analysis.

Alkane C-H bond activation by various catalysts and enzymes has attracted considerable attention recently, but many issues are still unanswered. The conversion of ethane to ethanol and ethene by bare [Fe(III)═O](+) has been explored using density functional theory and coupled-cluster method comprehensively. Two possible reaction mechanisms are available for the entire reaction, the direct H-abstraction mechanism and the concerted mechanism. First, in the direct H-abstraction mechanism, a direct H-abstraction is encountered in the initial step, going through a collinear transition state C···H···O-Fe and then leading to the generation of an intermediate Fe-OH bound to the alkyl radical weakly. The final product of the direct H-abstraction mechanism is ethanol, which is produced by the hydroxyl group back transfer to the carbon radical. Second, in the concerted reaction mechanism, the H-abstraction process is characterized via overcoming four/five-centered transition states (6/4)TSH_c5 or (4)TSH_c4. The second step of the concerted mechanism can lead to either product ethanol or ethene. Moreover, the major product ethene can be obtained through two different pathways, the one-step pathway and the stepwise pathway. It is the first report that the former pathway starting from (6/4)IM_c to the product can be better described as a proton-coupled electron transfer (PCET). It plays an important role in the product ethene generation according to the CCSD(T) results. The spin-orbital coupling (SOC) calculations demonstrate that the title reaction should proceed via a two-state reactivity (TSR) pattern and that the spin-forbidden transition could slightly lower the rate-determining energy barrier height. This thorough theoretical study, especially the explicit electronic structure analysis, may provide important clues for understanding and studying the C-H bond activation promoted by iron-based artificial catalysts.

Mechanism of benzene hydroxylation by high-valent bare Fe(IV)=O2+: explicit electronic structure analysis.

The conversion of benzene to phenol by high-valent bare FeO(2+) was comprehensively explored using a density functional theory method. The conductor-like screen model (COSMO) was used to mimic the role of solvent effect with acetonitrile chosen as the solvent. Two radical mechanisms and one oxygen insertion mechanism were tested for this conversion. The first radical mechanism can also be named as the concerted mechanism in which the hydrogen-atom abstraction process is accomplished via a four-centered transition state. The second radical mechanism is initiated by a direct hydrogen-atom abstraction with a collinear C-H-O transition structure. It is actually the same as the well-accepted rebound mechanism for the C-H bond activation by heme and nonheme iron-oxo catalysts. The third is an oxygen insertion mechanism which is essentially an aromatic electrophilic attack leading to an arenium σ-complex intermediate. The formation of a precomplex with an η(4) coordinate environment in the first radical mechanism is energetically more favorable. However, the relatively lower activation energy barrier of the oxygen insertion mechanism compared to the radical ones makes it highly competitive if the Fe=O(2+) collides with benzene in the proper orientation. The detailed potential energy surfaces also indicate that the second radical mechanism, i.e., the benzene C-H bond activation through the rebound mechanism, is less favorable. This thorough theoretical study, especially the electronic structure analysis, may offer very important clues for understanding and studying C-H bond activation by iron-based catalysts and enzymatic reactions in protein active pockets.

Alkali metal atom-aromatic ring: a novel interaction mode realizes large first hyperpolarizabilities of M@AR (M=Li, Na, and K, AR=pyrrole, indole, thiophene, and benzene).

Several new electride compounds M@pyrrole (M = Li, Na, and K), Li@AR (AR = indole, thiophene, and benzene), Li@tryptophan and Li@serotonin were designed and investigated, which exhibit considerably large first hyperpolarizabilities (ß(0)) (6705, 1116, 11399, 5781, 4808, 1536, 8106, and 9389 au, respectively) by comparison with their corresponding sole molecules pyrrole (ß(0) = 30 au), indole (104 au), thiophene (6 au), benzene (0 au), tryptophan (159 au) and serotonin (151 au), respectively. The computational results revealed that the interaction of the alkali metal atom with π-conjugated aromatic ring (AR) is one effectively new approach to produce diffuse excess electron to get a large ß(0) value, which is advantageous for the design of the novel high-performance NLO materials with π-conjugated AR: alkali metal atoms doped nanomaterials and biomolecules.

Theoretical mechanistic study of the reaction of the methylidyne radical with methylacetylene.

A detailed doublet potential energy surface for the reaction of CH with CH(3)CCH is investigated at the B3LYP/6-311G(d,p) and G3B3 (single-point) levels. Various possible reaction pathways are probed. It is shown that the reaction is initiated by the addition of CH to the terminal C atom of CH(3)CCH, forming CH(3)CCHCH 1 (1a,1b). Starting from 1 (1a,1b), the most feasible pathway is the ring closure of 1a to CH(3)-cCCHCH 2 followed by dissociation to P ( 3 )(CH(3)-cCCCH+H), or a 2,3 H shift in 1a to form CH(3)CHCCH 3 followed by C-H bond cleavage to form P ( 5 )(CH(2)CHCCH+H), or a 1,2 H-shift in 1 (1a, 1b) to form CH(3)CCCH(2) 4 followed by C-H bond fission to form P ( 6 )(CH(2)CCCH(2)+H). Much less competitively, 1 (1a,1b) can undergo 3,4 H shift to form CH(2)CHCHCH 5. Subsequently, 5 can undergo either C-H bond cleavage to form P ( 5 ) (CH(2)CHCCH+H) or C-C bond cleavage to generate P ( 7 ) (C(2)H(2)+C(2)H(3)). Our calculated results may represent the first mechanistic study of the CH + CH(3)CCH reaction, and may thus lead to a deeper understanding of the title reaction.

Direct ab initio dynamics study of radical C4H (X̃2Σ+) + CH4 reaction.

The methane (CH(4)) hydrogen abstraction reaction by linear butadiynyl radical C(4)H (CCCCH) has been investigated by direct ab initio dynamics over a wide temperature range of 100-3000 K, theoretically. The potential energy surfaces (PESs) have been constructed at the CCSD(T)/aug-cc-pVTZ//BB1K/6-311G(d,p) levels of theory. Two different hydrogen abstraction channels by C(1) and C(4) of C(4)H (C(1)C(2)C(3)C(4)H) have been considered. The results indicate that the C(1) position of C(4)H is a more reactive site. The electron transfer behaviors of two possible channels are also analyzed by quasi-restricted orbital (QRO) in detail. The rate constants calculated by canonical variational transition-state theory (CVT) with the small-curvature tunneling correction (SCT) are in excellent agreement with available experimental values. The normal and three-parameter expressions of Arrhenius rate constants are also provided within 100-3000 K. It is expected to be helpful for further studies on the reaction dynamics behaviors over a wide temperature range where no experimental data is available so far.

Exceptionally large second-order nonlinear optical response in donor-graphene nanoribbon-acceptor systems.

Graphene nanoribbon (GNR) has been used, for the first time, as an excellent conjugated bridge in a donor-conjugated bridge-acceptor (D-B-A) framework to design high-performance second-order nonlinear optical materials. Owing to the unique diradical planar conjugated bridge of GNR, D(NH(2))-GNR-A(NO(2)) exhibits exceptionally large static first hyperpolarizability (ß(0)) up to 2.5×10(6) a.u. (22000×10(-30) esu) for H(2)N-(7,3)ZGNR-NO(2) (ZGNR=zigzag-edged GNR), which is about 15 times larger than the recorded value of ß(0) (1470×10(-30) esu) for the D-A polyene reported by Blanchard-Desce et al. [Chem. Eur. J. 1997, 3, 1091]. Interestingly, we have found that the size effect of GNR plays a key role in increasing ß(0) for the H(2)N-GNR-NO(2) system, in which the width effect of GNR perpendicular to the D-A direction is superior to the length effect along the D-A direction.

Electric field-driven acid-base chemistry: proton transfer from acid (HCl) to base (NH3/H2O).

It is well-known that single H3N-HCl and H2O-HCl acid-base pairs do not react to form the ion pairs, H4N(+)Cl(-) and H3O(+)Cl(-), in isolation. On the basis of ab initio method, we propose a physical method of external electric field (Eext) to drive the proton transfer from acid (HCl) to base (NH3/H2O). Our results show that when Eext along the proton-transfer direction achieves or exceeds the critical electric field (Ec), the proton transfer occurs, such as, the Ec values of proton transfer for H3N-HCl and H2O-HCl are 54 × 10(-4) and 210 × 10(-4) au, respectively. And the degree of the proton transfer can be controlled by modulating the strength of Eext. Furthermore, we estimate the inductive strength of an excess electron (Ee) equivalent to the Eext = 125 × 10(-4) au, which is greater than the Ec (54 × 10(-4) au) of NH3-HCl but less than the Ec (210 × 10(-4) au) of H2O-HCl. This explains well the anion photoelectron spectroscopy [Eustis et al. Science 2008, 319, 936] that an excess electron can trigger the proton transfer for H3N-HCl but not for H2O-HCl. On the basis of the above estimation, we also predict that two excess electrons can induce H2O-HCl to undergo the proton transfer and form the ion pair H3O(+)Cl(-).

Ab initio investigation on a new class of binuclear superalkali cations M2Li(2k+1)+ (F2Li3+, O2Li5+, N2Li7+, and C2Li9+).

Superalkalies with low ionization potentials (IPs) can exhibit behaviors reminiscent of alkali atoms and hence be considered as potential building blocks for the assembly of novel nanostructured materials. A new series of binuclear superalkali cations M(2)Li(2k+1)(+) (M = F, O, N, C) has been studied using ab initio methods. The structural features of such cations are found to be related to the central atoms. In the preferred structures of F(2)Li(3)(+), O(2)Li(5)(+), and N(2)Li(7)(+), two central atoms are bridged by lithium atoms. While in the global minima of C(2)Li(9)(+), two central carbon atoms directly link each other and the C-C unit extends to the surface of the whole system. These M(2)Li(2k+1)(+) species exhibit very low vertical electron affinities of 2.74-4.61 eV at the OVGF/6-311+G(3df) level and hence should be classified as superalkali cations.

Reaction mechanism of CH + C(3)H(6): a theoretical study.

A detailed theoretical study is performed at the B3LYP/6-311G(d,p) and G3B3 (single-point) levels as an attempt to explore the reaction mechanism of CH with C(3)H(6). It is shown that the barrierless association of CH with C(3)H(6) forms two energy-rich isomers CH(3)-cCHCHCH(2) (1), and CH(2)CH(2)CHCH(2) (4). Isomers 1 and 4 are predicted to undergo subsequent isomerization and dissociation steps leading to ten dissociation products P(1) (CH(3)-cCHCHCH + H), P(2) (CH(3)-cCCHCH(2) + H), P(3) (cCHCHCH(2) + CH(3)), P(4) (CH(3)CHCCH(2) + H), P(5) (cis-CH(2)CHCHCH(2) + H), P(6) (trans-CH(2)CHCHCH(2) + H), P(7) (C(2)H(4) + C(2)H(3)), P(8) (CH(3)CCH + CH(3)), P(9) (CH(3)CCCH(3) + H) and P(12) (CH(2)CCH(2) + CH(3)), which are thermodynamically and kinetically possible. Among these products, P(5), P(6), and P(7) may be the most favorable products with comparable yields; P(1), P(2), and P(3) may be the much less competitive products, followed by the almost negligible P(4), P(8), P(9), and P(12). Since the isomers and transition states involved in the CH + C(3)H(6) reaction all lie lower than the reactant, the title reaction is expected to be fast, which is consistent with the measured large rate constant in experiment. The present study may lead us to a deep understanding of the CH radical chemistry.

Releasing of the chromophore from the drug delivery protein C-1027: a molecular dynamics simulations study.

The aromatized chromophore (Chr) of C-1027 with selective DNA-cleaving ability, which is stabilized and delivered by the apoprotein (Apo) in vitro, is not released until the holoprotein (Apo+Chr) penetrates into the cultured cancer cells. As a drug delivery system, the holoprotein has gained much attention in clinical application. However, the Chr-releasing mechanism is ambiguous so far. In this paper, the releasing pathway is investigated using conventional molecular dynamics (MD), essential dynamics (ED), essential dynamics sampling and steered molecular dynamics (SMD) simulations. The results indicate that the releasing paths are related to the local motions of three loops: L3 (Val39-Gln42), L7 (Thr75-Thr79) and L9 (Asn97-Leu100). The major obstacles to Chr releasing come from steric hindrance, direct hydrogen bonds and hydrophobic interactions formed by the three loops, and Ser98 is an important residue in the releasing process. The most favorable direction of releasing is almost parallel to the connection between L7 and L3. Releasing from the direction, Chr only needs to break three hydrogen bonds from Ser98 and Pro76 and the weakest steric hindrance.

Lithium bonding interaction hyperpolarizabilities of various li-bond dimers.

The effects of intermolecular interaction on dipole moment (mu(z)), the mean (alpha(0)) and anisotropy (Deltaalpha) of the polarizability, and the first and second hyperpolarizabilities (beta(0) and gamma(0), respectively) for four lithium-bond dimers (LiCN...LiCN, LiNC...LiNC, H(4)C(2)...LiF, and H(3)N...LiF) have been investigated in the finite-field approach. The electric properties were obtained at the CCSD(T)/6-311++G(2df, 2p) level. For the four dimers, electron correlation contributions are very important to the total and interaction static electric properties. Different from the H bond interaction effects on hyperpolarizabilities of H-bond dimers, the Li-bond interactions significantly decrease the beta(0) values of the four Li-bond dimers (by 73.6% for LiCN...LiCN, by 204.8% for LiNC...LiNC, by 75.5% for H(4)C(2)...LiF, and by 24.0% for H(3)N...LiF), and also considerably decrease the second hyperpolarizabilities of the Li-bond dimers investigated (by 52.7% for LiCN...LiCN, by 43.7% for LiNC...LiNC, by 16.4% for H(4)C(2)...LiF, and by 62.6% for H(3)N...LiF).

Theoretical mechanistic study on the ion-molecule reaction of CHCl- with CS2.

A detailed theoretical study for the poorly understood ion-molecule reaction of CHCl(-) with CS(2) is explored at the B3LYP/6-311++G(d,p) and CCSD(T)/6-311++G(3df,2p) (single-point) levels. Various possible reaction pathways are considered. On the doublet potential energy surface, five dissociation products are both thermodynamically and kinetically possible. Among these products, P(7) (SCHCl(-) + CS) may be the most favorable product with predominant abundances, whereas P(1) (Cl(-) + SCHCS) and P(2) (Cl(-) + HCCSS) may be the second and third feasible products followed by the almost negligible P(3) (Cl(-) + HSCCS), P(4) (CClS(-) + HCS), and P(6) (S-cCCS(-) + HCl). Because the isomers and transition states involved in the most feasible pathways all lie below the reactant, the title reaction is expected to be fast, which is consistent with the measured large rate constant in recent experiment. The present paper may provide a useful guide for understanding other analogous ion-molecule reactions such as CHF(-) and CHBr(-) with CS(2), COS, and CO(2).

Molecular dynamics simulations investigation of neocarzinostatin chromophore-releasing pathways from the holo-NCS protein.

The enediyne ring chromophore with strong DNA cleavage activity of neocarzinostatin is labile and therefore stabilization by forming the complex (carrying protein+chromophore: holo-NCS). Holo-NCS has gained much attention in clinical use as well as for drug delivery systems, but the chromophore-releasing mechanism to trigger binding to the target DNA with high affinity and producing DNA damage remain unclear. Three possible pathways were initially determined by conventional MD, essential dynamics and essential dynamics sampling. One of the paths runs along the naphthoate moiety; another runs along the amino sugar moiety; the third along the enediyne ring. Further, calculated forces and time by FPMD (force-probe molecular dynamics) suggest that the opening of the naphthoate moiety is most favorable pathway and Leu45, Phe76 and Phe78 all are key residues for chromophore release. In addition, conformational analyses indicate that the chromophore release is only local motions for the protein.