Structural Dynamics and Catalytic Mechanism of ATP13A2 (PARK9) from Simulations

ATP13A2 is a gene encoding a protein of the P5B subfamily of ATPases and is a PARK gene. Molecular defects of the gene are mainly associated with variations of Parkinson’s disease (PD). Despite the established importance of the protein in regulating neuronal integrity, the three-dimensional structure of the protein currently remains unresolved crystallographically. We have modeled the structure and reactivity of the full-length protein in its E1-ATP state. Using molecular dynamics (MD), quantum cluster, and quantum mechanical/molecular mechanical (QM/MM) methods, we aimed at describing the main catalytic reaction, leading to the phosphorylation of Asp513. Our MD simulations suggest that two positively charged Mg2+ cations are present at the active site during the catalytic reaction, stabilizing a specific triphosphate binding mode. Using QM/MM calculations, we subsequently calculated the reaction profiles for the phosphoryl transfer step in the presence of one and two Mg2+ cations. The calculated barrier heights in both cases are found to be ∼12.5 and 7.5 kcal mol–1, respectively. We elucidated details of the catalytically competent ATP conformation and the binding mode of the second Mg2+ cofactor. We also examined the role of the conserved Arg686 and Lys859 catalytic residues. We observed that by significantly lowering the barrier height of the ATP cleavage reaction, Arg686 had major effect on the reaction. The removal of Arg686 increased the barrier height for the ATP cleavage by more than 5.0 kcal mol–1 while the removal of key electrostatic interactions created by Lys859 to the γ-phosphate and Asp513 destabilizes the reactant state. When missense mutations occur in close proximity to an active site residue, they can interfere with the barrier height of the reaction, which can halt the normal enzymatic rate of the protein. We also found large binding pockets in the full-length structure, including a transmembrane domain pocket, which is likely where the ATP13A2 cargo binds

Dynamic regulation of RAS and RAS signaling

RAS proteins regulate most aspects of cellular physiology. They are mutated in 30% of human cancers and 4% of developmental disorders termed Rasopathies. They cycle between active GTP-bound and inactive GDP-bound states. When active, they can interact with a wide range of effectors that control fundamental biochemical and biological processes. Emerging evidence suggests that RAS proteins are not simple on/off switches but sophisticated information processing devices that compute cell fate decisions by integrating external and internal cues. A critical component of this compute function is the dynamic regulation of RAS activation and downstream signaling that allows RAS to produce a rich and nuanced spectrum of biological outputs. We discuss recent findings how the dynamics of RAS and its downstream signaling is regulated. Starting from the structural and biochemical properties of wild-type and mutant RAS proteins and their activation cycle, we examine higher molecular assemblies, effector interactions and downstream signaling outputs, all under the aspect of dynamic regulation. We also consider how computational and mathematical modeling approaches contribute to analyze and understand the pleiotropic functions of RAS in health and disease

Estetika Musik Zapin sebagai Budaya Populer di Pekanbaru

Music Zapin in Pekanbaru as popular culture is a phenomenon of shifting concept, form, function, aesthetics and meaning to community supporters. Pendekonstruksian certain patterns (traditions to uniformity, standardization, imaging, capitalism, creativity and innovation of artists. Practically it is a form of creativity and innovation in the work of artists, both regard the development or preservation of Malay culture and art. Zapin music as popular culture has a postmodern aesthetic, including: parody, pastiche, parody, kitsch, camp, and schizophrenia. Zapin music performances shifting values keteradisiannya (traditional aesthetic concept ) to the modern aesthetic and even postmodern. The shift is due to social change Pekanbaru. Openness and homogenitasan, both ethnic and cultural openness menciptakaan Zapin space for musical performances to adapt to the space and the needs of society. Therefore, musical performances Zapin as popular culture (aesthetic profane)

Fenomena Hubungan Mamak dan Kemenakan di Minangkabau dalam Film Fiksi Drama Komedi “Lah Ka Jodoh”

His comedy-Drama Lah ka jodoh was inspired by the phenomenon of Mate Ka culture society Minang, about the relationship between Kemanakan and Mamak. In the comedy-drama Lah Ka Jodoh, which Mak Jala was long gone to wander down to the ground and the female Lord of Java. Mak Jala had a son named Rina, as long-stay in other cities, Mak Jala immediately returned to the village to introduce his son Rina to nephew named Khairul, but because it doesn't know to fix her Mak Jala with her niece's own maid, so here there is a polemic in his life when it was in vilage. Great themes in this movie is how when the film was screened to get empathy that can be taken home by the audience that the conflict could momentarily nieces mamak forgotten. His comedy-drama Lah Ka Jodoh in building Hoerijah Adam Performances shown ISI Padangpanjang in the face with the main building. With the show one scene that exists in the fictional Film Comedy Lah Ka Jodoh was on stage as the opening towards the film screenings.The process of designing is done through several stages. The first phase, the search script and story ideas, the second phase do the casting, forming the third stage crew, stage four hunting locations, the fifth stage of the exercises, the sixth phase of the preparation of the seventh set stage equipment, and location shooting, the eighth stage of the ninth stage of the preview, editing, tenth stage of film screenings

A simplified charge projection scheme for long-range electrostatics in ab initio QM/MM calculations

In a previous work [Pan et al., Molecules 23, 2500 (2018)], a charge projection scheme was reported, where outer molecular mechanical (MM) charges [>10 Å from the quantum mechanical (QM) region] were projected onto the electrostatic potential (ESP) grid of the QM region to accurately and efficiently capture long-range electrostatics in ab initio QM/MM calculations. Here, a further simplification to the model is proposed, where the outer MM charges are projected onto inner MM atom positions (instead of ESP grid positions). This enables a representation of the long-range MM electrostatic potential via augmentary charges (AC) on inner MM atoms. Combined with the long-range electrostatic correction function from Cisneros et al. [J. Chem. Phys. 143, 044103 (2015)] to smoothly switch between inner and outer MM regions, this new QM/MM-AC electrostatic model yields accurate and continuous ab initio QM/MM electrostatic energies with a 10 Å cutoff between inner and outer MM regions. This model enables efficient QM/MM cluster calculations with a large number of MM atoms as well as QM/MM calculations with periodic boundary conditions

Nanoscale investigation of polymer cement concretes by small angle neutron scattering

An analysis of dense cements, such as polymer cement concrete, is made to produce original innovative components for different types of constructing materials. These materials present good functional properties (ageing resistance, crack formation resistance, hardness, and stability of mechanical modules) and can be used for various applications. In this paper, experimental tests on Portland cement with added γ-Al 2 O 3 and redispersible dry polymer performed using small angle neutron scattering are reported. The objective of the investigation was to assess the key parameters of the material (e.g., porosity, fractal dimensions, and size distribution) at the nanoscale level as well as to obtain useful structural information for expanding the possibility of applications. The results obtained can contribute to the optimisation of the consistency of the material, the design of operating conditions of elements of structures and facilities, and the design of the procedures that support ecological criteria and enhance quality and safety levels. © 2017 Walter de Gruyter GmbH, Berlin/Boston

Molecular Screening for Terahertz Detection with Machine-Learning-Based Methods

The molecular requirements are explored for achieving efficient signal up-conversion in a recently developed technique for terahertz (THz) detection based on molecular optomechanics. We discuss which molecular and spectroscopic properties are most important for predicting efficient THz detection and outline a computational approach based on quantum-chemistry and machine-learning methods for calculating these properties. We validate this approach by bulk and surface-enhanced Raman scattering and infrared absorption measurements. We develop a virtual screening methodology performed on databases of millions of commercially available compounds. Quantum-chemistry calculations for about 3000 compounds are complemented by machine-learning methods to predict applicability of 93 000 organic molecules for detection. Training is performed on vibrational spectroscopic properties based on absorption and Raman scattering intensities. Our top molecules have conversion intensity two orders of magnitude higher than an average molecule from the database. We also discuss how other properties like molecular shape and self-assembling properties influence the detection efficiency. We identify molecular moieties whose presence in the molecules indicates high activity for THz detection and show an example where a simple modification of a frequently used self-assembling compound can enhance activity 85-fold. The capabilities of our screening method are demonstrated on narrow-band and broadband detection examples, and its possible applications in surface-enhanced spectroscopy are also discussed

Joint neutron/X-ray crystal structure of a mechanistically relevant complex of perdeuterated urate oxidase and simulations provide insight into the hydration step of catalysis

Cofactor-independent urate oxidase (UOX) is an ~137 kDa tetrameric enzyme essential for uric acid (UA) catabolism in many organisms. UA is first oxidized by O2 to dehydroisourate (DHU) via a peroxo intermediate. DHU then undergoes hydration to 5-hydroxyisourate (5HIU). At different stages of the reaction both catalytic O2 and water occupy the 'peroxo hole' above the organic substrate. Here, high-resolution neutron/X-ray crystallographic analysis at room temperature has been integrated with molecular dynamics simulations to investigate the hydration step of the reaction. The joint neutron/X-ray structure of perdeuterated Aspergillus flavus UOX in complex with its 8-azaxanthine (8AZA) inhibitor shows that the catalytic water molecule (W1) is present in the peroxo hole as neutral H2O, oriented at 45° with respect to the ligand. It is stabilized by Thr57 and Asn254 on different UOX protomers as well as by an O-H∙ ∙ ∙π interaction with 8AZA. The active site Lys10-Thr57 dyad features a charged Lys10-NH3+ side chain engaged in a strong hydrogen bond with Thr57OG1, while the Thr57OG1-HG1 bond is rotationally dynamic and oriented toward the π system of the ligand, on average. Our analysis offers support for a mechanism in which W1 performs a nucleophilic attack on DHUC5 with Thr57HG1 central to a Lys10-assisted proton-relay system. Room-temperature crystallography and simulations also reveal conformational heterogeneity for Asn254 that modulates W1 stability in the peroxo hole. This is proposed to be an active mechanism to facilitate W1/O2 exchange during catalysis

Mechanistic study of an immobilized molecular electrocatalyst by in situ gap-plasmon-assisted spectro-electrochemistry

Immobilized first-row transition metal complexes are potential low-cost electrocatalysts for selective CO2 conversion in the production of renewable fuels. Mechanistic understanding of their function is vital for the development of next-generation catalysts, although the poor surface sensitivity of many techniques makes this challenging. Here, a nickel bis(terpyridine) complex is introduced as a CO2 reduction electrocatalyst in a unique electrode geometry, sandwiched by thiol-anchoring moieties between two gold surfaces. Gap-plasmon-assisted surface-enhanced Raman scattering spectroscopy coupled with density functional theory calculations reveals that the nature of the anchoring group plays a pivotal role in the catalytic mechanism. Our in situ spectro-electrochemical measurement enables the detection of as few as eight molecules undergoing redox transformations in individual plasmonic hotspots, together with the calibration of electrical fields via vibrational Stark effects. This advance allows rapid exploration of non-resonant redox reactions at the few-molecule level and provides scope for future mechanistic studies of single molecules

Mechanistic study of an immobilized molecular electrocatalyst by in situ gap-plasmon-assisted spectro-electrochemistry

Immobilised first-row transition metal complexes are potential low-cost electrocatalysts for selective CO2 conversion to produce renewable fuels. Mechanistic understanding of their function is vital for the development of next-generation catalysts, though poor surface sensitivity of many techniques makes this challenging. Here, a nickel bis(terpyridine) complex is introduced as a CO2 reduction electrocatalyst in a unique electrode geometry, sandwiched by thiol anchoring moieties between two gold surfaces. Gap-plasmon-assisted surface-enhanced Raman scattering spectroscopy coupled with density functional theory calculations reveals the nature of the anchoring group plays a pivotal role in the catalytic mechanism by eliminating ligand loss. Our in-situ spectro-electrochemical measurement enables the detection of as few as 8 molecules undergoing redox transformations in the individual gold-sandwiched nanocavities, together with the calibration of electrical fields via vibrational Stark effects. This advance allows rapid exploration of non-resonant redox reactions at the few-molecule level and provides scope for future mechanistic studies of single-molecules