A Carbonate-Templated Decanuclear Mn Nanocage with Two Different Silsesquioxane Ligands.

The mild reaction of the preorganized silsesquioxane precursor with Mn(II) acetate under ambient conditions results in a mixed-valent {MnII6MnIII4} nanocage (SD/Mn10) which is protected by both acyclic trimer [Si3] and cyclic tetramer [Si4]. Serendipitous capture of atmospheric CO2 as a µ5-carbonate anion placed at the center supports the formation of the cluster. The magnetic analysis reveals the strong antiferromagnetic interactions between Mn ions. Moreover, the drop-casting film of SD/Mn10 shows photoelectric activity indicating its great potential as a semiconductor for photoelectric conversion applications.

Mutation-Induced Impacts on the Switch Transformations of the GDP- and GTP-Bound K-Ras: Insights from Multiple Replica Gaussian Accelerated Molecular Dynamics and Free Energy Analysis.

Mutations yield significant effect on the structural flexibility of two switch domains, SW1 and SW2, in K-Ras, which is considered as an important target of anticancer drug design. To unveil a molecular mechanism with regard to mutation-mediated tuning on the activity of K-Ras, multiple replica Gaussian accelerated molecular dynamics (MR-GaMD) simulations followed by analysis of free energy landscapes (FELs) are performed on the GDP- and GTP-bound wild-type (WT), G12V, and D33E K-Ras. The results suggest that G12V and D33E not only evidently change the flexibility of SW1 and SW2 but also greatly affect correlated motions of SW1 and SW2 separately relative to the P-loop and SW1, which exerts a certain tuning on the activity of K-Ras. The information stemming from the analyses of FELs reveals that the conformations of SW1 and SW2 are in high disorders in the GDP- and GTP-associated WT and mutated K-Ras, possibly producing significant effect on binding of guanine nucleotide exchange factors or effectors to K-Ras. The interaction networks of GDP and GTP with K-Ras are identified and the results uncover that the instability in hydrogen-bonding interactions of SW1 with GDP and GTP is mostly responsible for conformational disorder of SW1 and SW2 as well as tunes the activity of oncogenic K-Ras.

Effect of mutations on binding of ligands to guanine riboswitch probed by free energy perturbation and molecular dynamics simulations.

Riboswitches can regulate gene expression by direct and specific interactions with ligands and have recently attracted interest as potential drug targets for antibacterial. In this work, molecular dynamics (MD) simulations, free energy perturbation (FEP) and molecular mechanics generalized Born surface area (MM-GBSA) methods were integrated to probe the effect of mutations on the binding of ligands to guanine riboswitch (GR). The results not only show that binding free energies predicted by FEP and MM-GBSA obtain an excellent correlation, but also indicate that mutations involved in the current study can strengthen the binding affinity of ligands GR. Residue-based free energy decomposition was applied to compute ligand-nucleotide interactions and the results suggest that mutations highly affect interactions of ligands with key nucleotides U22, U51 and C74. Dynamics analyses based on MD trajectories indicate that mutations not only regulate the structural flexibility but also change the internal motion modes of GR, especially for the structures J12, J23 and J31, which implies that the aptamer domain activity of GR is extremely plastic and thus readily tunable by nucleotide mutations. This study is expected to provide useful molecular basis and dynamics information for the understanding of the function of GR and possibility as potential drug targets for antibacterial.

Mutation-mediated influences on binding of anaplastic lymphoma kinase to crizotinib decoded by multiple replica Gaussian accelerated molecular dynamics.

Anaplastic lymphoma kinase (ALK) has been thought to be a prospective target of anti-drug resistance design in treatment of tumors and specific neuron diseases. It is highly useful for the seeking of possible strategy alleviating drug resistance to probe the mutation-mediated effect on binding of inhibitors to ALK. In the current work, multiple replica Gaussian accelerated molecular dynamics (MR-GaMD) simulations, molecular mechanics generalized Born surface area (MM-GBSA) and free energy landscapes were coupled to explore influences of mutations L1198F, L1198F/C1156Y, and C1156Y on the binding of the first ALK inhibitor crizotinib to ALK. The results suggest that three mutations obviously affect structural flexibility, motion modes and conformational changes of ALKs. L1198F and L1198F/C1156Y strengthen the binding of crizotinib to the mutated ALKs but C1156Y induces evident drug resistance toward crizotinib. Analyses of free energy landscapes show that stability in the orientation and positions of crizotinib relative to ALK plays a vital role in alleviating drug resistance of mutations toward crizotinib. Residue-based free energy decomposition method was utilized to evaluate the contributions of separate residues to the binding of crizotinib. The results not only indicate that the tuning of point mutation L1198F on interaction networks of crizotinib with ALK can be regarded as a possible strategy to relieve drug resistance of the mutated ALK but also further verify that residues L1122, V1130, L1196, L1198, M1199, and L1256 can be used as efficient targets of anti-drug resistance design induced by mutations.

Unveiling conformational dynamics changes of H-Ras induced by mutations based on accelerated molecular dynamics.

Uncovering molecular basis with regard to the conformational change of two switches I and II in the GppNHp (GNP)-bound H-Ras is highly significant for the understanding of Ras signaling. For this purpose, accelerated molecular dynamics (aMD) simulations and principal component (PC) analysis are integrated to probe the effect of mutations G12V, T35S and Q61K on conformational transformation between two switches of the GNP-bound H-Ras. The RMSF and cross-correlation analyses suggest that three mutations exert a vital effect on the flexibility and internal dynamics of two switches in the GNP-bound H-Ras. The results stemming from PC analysis indicate that two switches in the GNP-bound WT H-Ras tend to form a closed state in most conformations, while those in the GNP-bound mutated H-Ras display transformation between different states. This conclusion is further supported by free energy landscapes constructed by using the distances of residues 12 away from 35 and 35 away from 61 as reaction coordinates and different experimental studies. Interaction scanning is performed on aMD trajectories and the information shows that conformational transformations of two switches I and II induced by mutations extremely affect the GNP-residue interactions. Meanwhile, the scanning results also signify that residues G15, A18, F28, K117, A146 and K147 form stable contacts with GNP, while residues D30, E31, Y32, D33, P34 and E62 in two switches I and II produce unstable contacts with GNP. This study not only reveals dynamic behavior changes of two switches in H-Ras induced by mutations, but also unveils general principles and mechanisms with regard to functional conformational changes of H-Ras.

Fabrication of ion doped WO3 photocatalysts through bulk and surface doping.

Na(+) doped WO3 nanowire photocatalysts were prepared by using post-treatment (surface doping) and in situ (bulk doping) doping methods. Photocatalytic degradation of Methyl Blue was tested under visible light irradiation, the results showed that 1wt.% Na(+) bulk-doped WO3 performed better, with higher photoactivity than surface-doped WO3. Photoelectrochemical characterization revealed the differences in the photocatalytic process for surface doping and bulk doping. Uniform bulk doping could generate more electron-hole pairs, while minimizing the chance of electron-hole recombination. Some bulk properties such as the bandgap, Fermi level and band position could also be adjusted by bulk doping, but not by surface doping.

Facile Preparation of Polysiloxane-Modified Asphalt Binder Exhibiting Enhanced Performance.

The development of polymer-modified asphalt (asphalt = asphalt binder) is significant because the polymer modifier can improve the performance of asphalt mixture and meet the requirements of the modern asphalt pavement. Herein, we present a novel polysiloxane-modified asphalt with enhanced performance, formed by simply mixing hydroxy-terminated polysiloxane (HO-PDMS) into base asphalt at 140 °C. The interaction mechanism of HO-PDMS in base asphalt was characterized by FT-IR, GPC, and DSC. It reveals that HO-PDMS polymers have been chemically bonded into the asphalt, and, thus, the resultant asphalt exhibits optimal compatibility and storage stability. The results based on fluorescence microscopy and a segregation test prove that HO-PDMS has good compatibility with base asphalt. Moreover, by virtue of the intriguing properties of polysiloxane, the present asphalt possesses improved low- and high-temperature properties, higher thermal stability, and enhanced hydrophobicity compared to conventional asphalt when using an appropriate dosage of HO-PDMS. DSC indicated that the Tg of modified asphalt (-12.8 °C) was obviously lower than that of base asphalt (-7.1 °C). DSR shows that the rutting parameter of modified asphalt was obviously higher than that of base asphalt. BBR shows that modified asphalt exhibited the lowest stiffness modulus and the highest creep rate with an HO-PDMS dosage of 6% and 4%, respectively. These results demonstrate that polysiloxane-modified asphalt can be promisingly utilized in realistic asphalt pavement with specific requirements, particularly high-/low-temperature resistance.

Binding mechanism of inhibitors to p38α MAP kinase deciphered by using multiple replica Gaussian accelerated molecular dynamics and calculations of binding free energies.

The p38α MAP Kinase has been an important target of drug design for treatment of inflammatory diseases and cancers. This work applies multiple replica Gaussian accelerated molecular dynamics (MR-GaMD) simulations and the molecular mechanics generalized Born surface area (MM-GBSA) method to probe the binding mechanism of inhibitors L51, R24 and 1AU to p38α. Dynamics analyses show that inhibitor bindings exert significant effect on conformational changes of the active helix α2 and the conserved DFG loop. The rank of binding free energies calculated with MM-GBSA not only agrees well with that determined by the experimental IC50 values but also suggests that mutual compensation between the enthalpy and entropy changes can improve binding of inhibitors to p38α. The analyses of free energy landscapes indicate that the L51, R24 and 1AU bound p38α display a DFG-out conformation. The residue-based free energy decomposition method is used to evaluate contributions of separate residues to the inhibitor-p38α binding and the results imply that residues V30, V38, L74, L75, I84, T106, H107, L108, M109, L167, F169 and D168 can be utilized as efficient targets of potent inhibitors toward p38α.

Conformational transformation of switch domains in GDP/K-Ras induced by G13 mutants: An investigation through Gaussian accelerated molecular dynamics simulations and principal component analysis.

Mutations in K-Ras are involved in a large number of all human cancers, thus, K-Ras is regarded as a promising target for anticancer drug design. Understanding the target roles of K-Ras is important for providing insights on the molecular mechanism underlying the conformational transformation of the switch domains in K-Ras due to mutations. In this study, multiple replica Gaussian accelerated molecular (MR-GaMD) simulations and principal component analysis (PCA) were applied to probe the effect of G13A, G13D and G13I mutations on conformational transformations of the switch domains in GDP-associated K-Ras. The results suggest that G13A, G13D and G13I enhance the structural flexibility of the switch domains, change the correlated motion modes of the switch domains and strengthen the total motion strength of K-Ras compared with the wild-type (WT) K-Ras. Free energy landscape analyses not only show that the switch domains of the GDP-bound inactive K-Ras mainly exist as a closed state but also indicate that mutations evidently alter the free energy profile of K-Ras and affect the conformational transformation of the switch domains between the closed and open states. Analyses of hydrophobic interaction contacts and hydrogen bonding interactions show that the mutations scarcely change the interaction network of GDP with K-Ras and only disturb the interaction of GDP with the switch (SW1). In summary, two newly introduced mutations, G13A and G13I, play similar adjustment roles in the conformational transformations of two switch domains to G13D and are possibly utilized to tune the activity of K-Ras and the binding of guanine nucleotide exchange factors.

Deciphering molecular mechanism behind conformational change of the São Paolo metallo-ß-lactamase 1 by using enhanced sampling.

The São Paolo metallo-ß-lactamase-1 (SPM-1) plays an important role in drug resistance of ß-lactam antibiotics and bindings of zinc ions produce significant effect on the conformations of SPM-1. Thus, it is of significance for understanding function of SPM-1 to probe the conformational changes of SPM-1 induced by bindings of zinc ions. Because replica-exchange molecular dynamics (REMD) simulations can efficiently improve conformational samplings of proteins, REMD and normal mode analysis (NMA) were performed on three systems, including SPM-1 with non-zinc ions, single zinc ion and double zinc ions, to decipher molecular mechanism of conformational changes for SPM-1. The results suggest that binding of double zinc ions induces a closed state of SPM-1, while SPM-1 with binding of non-zinc and single zinc ion mainly exists as an open conformation. The analysis of interaction network between residues was carried out by using the program Ring 2.0. The results show that binding of double zinc ions highly enhances the stability of the π-π interaction network consisting of F60, Y61, F82, F152, Y153 and Y226, two hydrogen bonds between E83 and R161 as well as the salt bridge interaction between E151 and K159 compared to the SPM-1 with non-zinc or single zinc ion, which better stabilizes the closed conformation of SPM-1. Thus, the closed conformation of SPM-1 induced by bindings of double zinc ions is important in catalysis and determining inhibitor selectivity. Meanwhile, this work may provide useful theoretical hints for design of potent inhibitors toward drug resistance of ß-lactam antibiotics.Communicated by Ramaswamy H. Sarma.

Decoding molecular mechanism of inhibitor bindings to CDK2 using molecular dynamics simulations and binding free energy calculations.

CDK2 can be used as an attractive target for development of efficient inhibitors curing multiple disease relating with CDK2. In this work, molecular dynamics (MD) simulations and binding free energy calculations were coupled to probe conformational changes of CDK2 due to inhibitor associations and binding mechanisms of inhibitors PM1, FMD and X64 to CDK2. The results suggest that the binding strength of FMD and X64 to CDK2 is stronger than that of PM1. Principal component (PC) analysis and cross-correlation map calculations based on the equilibrated MD trajectories demonstrate that the structural difference in inhibitors exerts important impact on motion modes and dynamics behavior of CDK2. Residue-based free energy decomposition method was adopted to estimate the inhibitor-residue spectrum. The results not only efficiently identify the hot interaction spot of inhibitors with CDK2 but also show that the hydrophobic rings R1, R2 and R3 as well as polar groups of three inhibitors play key roles in favorably binding of inhibitors to CDK2. This work is expected to contribute energetic basis and dynamics information to development of promising inhibitors toward CDK2.Communicated by Ramaswamy H. Sarma.

Binding modes and conformational changes of FK506-binding protein 51 induced by inhibitor bindings: insight into molecular mechanisms based on multiple simulation technologies.

The FK506-binding protein 51 (FKBP51) is a cochaperone that modulates the signal transduction of steroid hormone receptors and has been involved in prostate cancer, indicating that FKBP51 is an attractive target of drug design curing the related cancers. In this work, multiple short molecular dynamics (MSMD) simulations are combined with MM-GBSA method to investigate binding modes of inhibitors 3JP, 3JR and 3JQ to FKBP51. The results show that the substitutions of diols (R)-19 and (S)-19 at the R position of 3JP strengthen binding of 3JR and 3JQ to FKBP51. Principal component (PC) analysis performed on the equilibrated MSMD trajectories suggests that three inhibitor bindings produce significant effect on dynamics behavior and conformational changes of the loops L1, L2 and the domain ß-L-α-L-ß in FKBP51. The calculations of residue-based free energy decomposition not only recognize the hot interaction spot of inhibitors with FKBP51, but also display that the substitutions of diols (R)-19 and (S)-19 at the R position of 3JP play significant role in stronger binding of 3JR and 3JQ to FKBP51 than 3JP. This work is expected to provide theoretical hints and molecular mechanism for design of highly efficient inhibitors toward FKBP51.

Molecular Mechanism of Binding Selectivity of Inhibitors toward BACE1 and BACE2 Revealed by Multiple Short Molecular Dynamics Simulations and Free-Energy Predictions.

The ß-amyloid cleaving enzymes 1 and 2 (BACE1 and BACE2) have been regarded as the prospective targets for clinically treating Alzheimer's disease (AD) in the last two decades. Thus, insight into the binding differences of inhibitors to BACE1 and BACE2 is of significance for designing highly selective inhibitors toward the two proteins. In this work, multiple short molecular dynamics (MSMD) simulations are coupled with the molecular mechanics generalized Born surface area (MM-GBSA) method to probe the binding selectivity of three inhibitors DBO, CS9, and SC7 on BACE1 over BACE2. The results show that the entropy effect plays a key role in selectivity identification of inhibitors toward BACE1 and BACE2, which determines that DBO has better selectivity toward BACE2 over BACE1, while CS9 and CS7 can more favorably bind to BACE1 than BACE2. The hierarchical clustering analysis based on energetic contributions of residues suggests that BACE1 and BACE2 share the common hot interaction spots. The residue-based free-energy decomposition method was applied to compute the inhibitor-residue interaction spectrum, and the results recognize four common binding subpockets corresponding to the different groups of inhibitors, which can be used as efficient targets for designing highly selective inhibitors toward BACE1 and BACE2. Therefore, these results provide a useful molecular basis and dynamics information for development of highly selective inhibitors targeting BACE1 and BACE2.

Inhibiting mechanism of small molecule toward the p53-MDM2 interaction: A molecular dynamic exploration.

Disruption of the p53-MDM2 interaction has been an efficient strategy to renew the function of wild-type p53. In this work, molecular dynamic simulations, molecular mechanics-generalized Born surface area method, and principal component analysis were combined to probe interaction mechanism of inhibitors 2TZ, 2U0, 2U1, 2U5, 2U6, and 2U7 with MDM2. The rank of our current predicted binding free energies is in agreement with that of the experimental values. The results demonstrate that the introductions of thiazole and pyridine rings into 2TZ as well as the change in the orientation of inhibitors lead to the increase in the polar interactions of 2U0, 2U1, 2U5, 2U6, and 2U7 with MDM2 relative to 2TZ. The information derived from principal component analysis suggests that inhibitor bindings produce significant effect on the binding cleft of MDM2 and make the binding cleft wider and bigger so as to accommodate different type inhibitors. This study is looked forward to contributing theoretical hints for designs of potent inhibitors targeting the p53-MDM2 interaction.

Dynamics revelation of conformational changes and binding modes of heat shock protein 90 induced by inhibitor associations.

Heat shock protein 90 (Hsp90) has been an attractive target of potential drug design for antitumor treatment. The current work integrates molecular dynamics (MD) simulations, calculations of binding free energy, and principal component (PC) analysis with scanning of inhibitor-residue interaction to probe the binding modes of inhibitors YK9, YKJ and YKI to Hsp90 and identify the hot spot of the inhibitor-Hsp90 binding. The results suggest that the introductions of two groups G1 and G2 into YKJ and YKI strengthen the binding ability of YKJ and YKI to Hsp90 compared to YK9. PC analysis based MD trajectories prove that inhibitor bindings exert significant effects on the conformational changes, internal dynamics and motion modes of Hsp90, especially for the helix α2 and the loops L1 and L2. The calculations of residue-based free energy decomposition and scanning of the inhibitor-Hsp90 interaction suggest that six residues L107, G108, F138, Y139, W162 and F170 construct the common hot spot of the inhibitor-residue interactions. Moreover the substitutions of the groups G1 and G2 in YKJ and YKI lead to two additional hydrogen bonding interactions and multiple hydrophobic interactions for bindings of YKJ and YKI to Hsp90. This work is also expected to contribute theoretical hints for the design of potent inhibitors toward Hsp90.

Ceria Nanotube Formed by Sacrificed Precursors Template through Oswald Ripening.

Controllable preparation of ceria nanotube was realized by hydrothermal treatment of Ce(OH)CO3 precursors. The gradually changing morphologies and microstructures of cerium oxide were characterized by X-ray powder diffraction, scanning electron microscopy and transmission electron microscopy. A top-down path is illuminated to have an insight to the morphological transformation from nanorod to nanotube by adjusting the reaction time. The growth process is investigated by preparing a series of intermediate morphologies during the shape evolution of CeO2 nanostructure based on the scanning electron microscopy image observation. On the basis of the time-dependent experimental observation, the possible formation mechanism related to oriented attachment and Oswald ripening was proposed, which might afford some guidance for the synthesis of other inorganic nanotubes.