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  • MDPI AG  (5)
  • 1
    Online Resource
    Online Resource
    Using Coarse-Grained Simulations to Characterize the Mechanisms of Protein–Protein Association
    MDPI AG ; 2020
    In:  Biomolecules Vol. 10, No. 7 ( 2020-07-15), p. 1056-
    Details
    In: Biomolecules, MDPI AG, Vol. 10, No. 7 ( 2020-07-15), p. 1056-
    Abstract: The formation of functionally versatile protein complexes underlies almost every biological process. The estimation of how fast these complexes can be formed has broad implications for unravelling the mechanism of biomolecular recognition. This kinetic property is traditionally quantified by association rates, which can be measured through various experimental techniques. To complement these time-consuming and labor-intensive approaches, we developed a coarse-grained simulation approach to study the physical processes of protein–protein association. We systematically calibrated our simulation method against a large-scale benchmark set. By combining a physics-based force field with a statistically-derived potential in the simulation, we found that the association rates of more than 80% of protein complexes can be correctly predicted within one order of magnitude relative to their experimental measurements. We further showed that a mixture of force fields derived from complementary sources was able to describe the process of protein–protein association with mechanistic details. For instance, we show that association of a protein complex contains multiple steps in which proteins continuously search their local binding orientations and form non-native-like intermediates through repeated dissociation and re-association. Moreover, with an ensemble of loosely bound encounter complexes observed around their native conformation, we suggest that the transition states of protein–protein association could be highly diverse on the structural level. Our study also supports the idea in which the association of a protein complex is driven by a “funnel-like” energy landscape. In summary, these results shed light on our understanding of how protein–protein recognition is kinetically modulated, and our coarse-grained simulation approach can serve as a useful addition to the existing experimental approaches that measure protein–protein association rates.
    Type of Medium: Online Resource
    ISSN: 2218-273X
    URL: Article
    DOI: 10.3390/biom10071056
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2701262-1
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  • 2
    Online Resource
    Online Resource
    Enhancement of the Al/Mg Dissimilar Friction Stir Welding Joint Strength with the Assistance of Ultrasonic Vibration
    MDPI AG ; 2021
    In:  Metals Vol. 11, No. 7 ( 2021-07-12), p. 1113-
    Details
    In: Metals, MDPI AG, Vol. 11, No. 7 ( 2021-07-12), p. 1113-
    Abstract: The assistance of ultrasonic vibration during the friction stir welding (FSW) process has been verified as an effective approach for the improvement of joint strength. In the present study, experimentation on Al/Mg dissimilar alloys in butt joint configuration is implemented by employing FSW with and without the assistance of ultrasonic vibration. An optimized tool shoulder diameter of 12 mm is utilized, and the ultrasonic vibration is applied perpendicularly onto the tool along the welding direction, which is named UVaFSW. The results of joint appearance and macrostructure, characteristics of the intermetallic compounds (IMCs), as well as joint strength and fracture appearance are compared between Al/Mg FSW joints with and without ultrasonic vibration. It is demonstrated that the material intermixing between Al and Mg alloys is substantially strengthened in the UVaFSW joint compared with that in the FSW joint. Additionally, the ultrasonic vibration can be beneficial for the reduction of IMC thickness, as well as the formation of intermittently distributed IMC phases at the Al–Mg bonding interface. Consequently, the mechanical properties of Al/Mg FSW joints are significantly improved with the assistance of ultrasonic vibration. The maximum ultimate tensile strength is 206 MPa at tool rotation speed of 800 rpm and welding speed of 50 mm/min for the Al/Mg UVaFSW joint.
    Type of Medium: Online Resource
    ISSN: 2075-4701
    URL: Article
    DOI: 10.3390/met11071113
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2662252-X
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  • 3
    Online Resource
    Online Resource
    A Systematic Test of Receptor Binding Kinetics for Ligands in Tumor Necrosis Factor Superfamily by Computational Simulations
    MDPI AG ; 2020
    In:  International Journal of Molecular Sciences Vol. 21, No. 5 ( 2020-03-05), p. 1778-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 21, No. 5 ( 2020-03-05), p. 1778-
    Abstract: Ligands in the tumor necrosis factor (TNF) superfamily are one major class of cytokines that bind to their corresponding receptors in the tumor necrosis factor receptor (TNFR) superfamily and initiate multiple intracellular signaling pathways during inflammation, tissue homeostasis, and cell differentiation. Mutations in the genes that encode TNF ligands or TNFR receptors result in a large variety of diseases. The development of therapeutic treatment for these diseases can be greatly benefitted from the knowledge on binding properties of these ligand–receptor interactions. In order to complement the limitations in the current experimental methods that measure the binding constants of TNF/TNFR interactions, we developed a new simulation strategy to computationally estimate the association and dissociation between a ligand and its receptor. We systematically tested this strategy to a comprehensive dataset that contained structures of diverse complexes between TNF ligands and their corresponding receptors in the TNFR superfamily. We demonstrated that the binding stabilities inferred from our simulation results were compatible with existing experimental data. We further compared the binding kinetics of different TNF/TNFR systems, and explored their potential functional implication. We suggest that the transient binding between ligands and cell surface receptors leads into a dynamic nature of cross-membrane signal transduction, whereas the slow but strong binding of these ligands to the soluble decoy receptors is naturally designed to fulfill their functions as inhibitors of signal activation. Therefore, our computational approach serves as a useful addition to current experimental techniques for the quantitatively comparison of interactions across different members in the TNF and TNFR superfamily. It also provides a mechanistic understanding to the functions of TNF-associated cell signaling pathways.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms21051778
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 4
    Online Resource
    Online Resource
    Fragility Analyses of Bridge Structures Using the Logarithmic Piecewise Function-Based Probabilistic Seismic Demand Model
    MDPI AG ; 2021
    In:  Sustainability Vol. 13, No. 14 ( 2021-07-13), p. 7814-
    Details
    In: Sustainability, MDPI AG, Vol. 13, No. 14 ( 2021-07-13), p. 7814-
    Abstract: Seismic fragility analysis is an efficient method to evaluate the structural failure probability during earthquake events. Among the existing fragility analysis methods, the probabilistic seismic demand model (PSDM) and the joint probabilistic seismic demand model (JPSDM) are generally used to compute the component and system fragility, respectively. However, the statistical significance behind the parameters related to the current PSDM and JPSDM are not comparable. Aside from that, when calculating the system fragility, the Monte Carlo sampling (MCS) method is time-consuming. To solve the two flaws, in this paper, the logarithm piecewise functions were used to generate the PSDM and the JPSDM, and the MCS was replaced by the univariate conditioning approximation (UCA) method. The concepts and application procedures of the proposed fragility analysis methods were elaborated first. Then, the UCA method was illustrated in detail. Finally, fragility curves of a steel arch truss case study bridge were generated by the proposed method. The research results indicate the following: (1) the proposed methods unify the data sources and statistical significance of the parameters used in the PSDM and the JPSDM; (2) the logarithmic piecewise function-based PSDM sensitively reflects the changing trend of the component’s demand with the fluctuation of the seismic intensity measure; (3) under transverse seismic waves, major injuries happen on the side bearings of the bridge, while slight damage may occur on each pier, and as the seismic intensity measure increases, the side bearings are more likely to be damaged; (4) for the severe damage and the absolute damage of the studied bridge, the system fragility curves are closer to the upper failure bounds; and (5) compared with the MSC method, the accuracy of the UCA method can be guaranteed with less calculation time.
    Type of Medium: Online Resource
    ISSN: 2071-1050
    URL: Article
    DOI: 10.3390/su13147814
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2518383-7
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  • 5
    Online Resource
    Online Resource
    Impacts of Defocusing Amount and Molten Pool Boundaries on Mechanical Properties and Microstructure of Selective Laser Melted AlSi10Mg
    MDPI AG ; 2018
    In:  Materials Vol. 12, No. 1 ( 2018-12-26), p. 73-
    Details
    In: Materials, MDPI AG, Vol. 12, No. 1 ( 2018-12-26), p. 73-
    Abstract: The influences of processing parameters such as volumetric energy density (ε) and, particularly, defocusing amount (DA) on densification, microstructure, tensile property, and hardness of the as-printed dense AlSi10Mg alloy by selective laser melting (SLM) were studied systematically. The molten pool boundaries (MPBs) were found overwhelmingly at regular and complex spatial topological structures affected by DA value to exist in two forms, while the “layer–layer” MPB overlay mutually and the “track–track” MPBs intersect to form acute angles with each other. The microstructure of MPBs exhibits a coarse grain zone near the MPBs and the characteristics of segregation of nonmetallic elements (O, Si) where the crack easily happened. The DA value (−2 to 2 mm) affected both the density and the tensile mechanical properties. High tensile strength (456 ± 14 MPa) and good tensile ductility (9.5 ± 1.4%) were achieved in the as-printed condition corresponding to DA = 0.5 mm. The tensile fracture surface features were analyzed and correlated to the influence of the DA values.
    Type of Medium: Online Resource
    ISSN: 1996-1944
    URL: Article
    DOI: 10.3390/ma12010073
    Language: English
    Publisher: MDPI AG
    Publication Date: 2018
    detail.hit.zdb_id: 2487261-1
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