scholarly journals Modulating long-range energetics via helix stabilization: a case study using T4 lysozyme

2018 ◽  
Author(s):  
Sabriya N. Rosemond ◽  
Kambiz M. Hamadani ◽  
Jamie H.D. Cate ◽  
Susan Marqusee
Keyword(s):  
Protein Folding ◽  
Long Range ◽  
Salt Bridge ◽  
Globular Protein ◽  
Full Length ◽  
T4 Lysozyme ◽  
Long Distance ◽  
Terminal Fragment ◽  
The Stability

Cooperative protein folding requires distant regions of a protein to interact and provide mutual stabilization. The mechanism of this long-distance coupling remains poorly understood. Here, we use T4 lysozyme (T4L*) as a model to investigate long-range communications across a globular protein. T4L* is composed of two structurally distinct subdomains, although it behaves in a two-state manner at equilibrium. The subdomains of T4L* are connected via two topological connections: the N-terminal helix that is structurally part of the C-terminal subdomain (the A-helix) and a long helix that spans both subdomains (the C-helix). To understand the role that the C-helix plays in cooperative folding, we analyzed a circularly permuted version of T4L* (CP13*), whose subdomains are connected only by the C-helix. We demonstrate that when isolated as individual fragments, both subdomains of CP13* can fold autonomously into marginally stable conformations. The energetics of the N-terminal subdomain depend on the formation of a salt bridge known to be important for stability in the full-length protein. We show that the energetic contribution of the salt bridge to the stability of the N-terminal fragment increases when the C-helix is stabilized, such as occurs upon folding of the C-terminal subdomain. These results suggest a model where long-range energetic coupling is mediated by helix stabilization.

scholarly journals Validation of a Long-Range Trajectory Model Using Gas Balloon Tracks from the Gordon Bennett Cup 95

1997 ◽  
Vol 36 (6) ◽  
pp. 711-720 ◽  
Author(s):  
Kathrin Baumann ◽  
Andreas Stohl
Keyword(s):  
Long Range ◽  
Computation Time ◽  
Wind Fields ◽  
Time Step ◽  
Long Distance ◽  
Trajectory Model ◽  
Trajectory Calculations ◽  
Stochastic Errors ◽  
Divergent Wind

Abstract In September 1995, 18 gas balloon teams competed at the Gordon Bennett Cup, a long-distance ballooning event. The landing positions, travel times of all teams, and detailed information on the tracks of four teams are available. A special version of the trajectory model FLEXTRA (flexible trajectories) is used that allows the heights of calculated trajectories to be adjusted to the respective balloon heights at every computation time step. The comparison of calculated and observed balloon trajectories allows a validation of the trajectory model. In this case study, the agreement between calculated and balloon trajectories was good, with average relative transport errors of less than 20% of the travel distance after 46 h of travel time. Most of the trajectory errors originate from interpolation errors and from amplifications of small position disturbances in divergent wind fields. Trajectory ensembles, taking into account stochastic errors occurring during the trajectory calculations, are shown to be very reliable in assessing the uncertainties of the computed trajectories. In the present study, the balloon tracks were enveloped by the ensemble trajectories most of the time, suggesting that errors in the analyzed wind fields were relatively small.

scholarly journals Structure of full-length human phenylalanine hydroxylase in complex with tetrahydrobiopterin

2019 ◽  
Vol 116 (23) ◽  
pp. 11229-11234 ◽  
Author(s):  
Marte Innselset Flydal ◽  
Martín Alcorlo-Pagés ◽  
Fredrik Gullaksen Johannessen ◽  
Siseth Martínez-Caballero ◽  
Lars Skjærven ◽  
...  
Keyword(s):  
Phenylalanine Hydroxylase ◽  
Genetic Disorder ◽  
Interaction Network ◽  
Salt Bridge ◽  
Full Length ◽  
Site Directed Mutagenesis ◽  
Pharmacological Chaperone ◽  
Key Enzyme ◽  
The Stability ◽  
Dynamics Simulations

Phenylalanine hydroxylase (PAH) is a key enzyme in the catabolism of phenylalanine, and mutations in this enzyme cause phenylketonuria (PKU), a genetic disorder that leads to brain damage and mental retardation if untreated. Some patients benefit from supplementation with a synthetic formulation of the cofactor tetrahydrobiopterin (BH4) that partly acts as a pharmacological chaperone. Here we present structures of full-length human PAH (hPAH) both unbound and complexed with BH4 in the precatalytic state. Crystal structures, solved at 3.18-Å resolution, show the interactions between the cofactor and PAH, explaining the negative regulation exerted by BH4. BH4 forms several H-bonds with the N-terminal autoregulatory tail but is far from the catalytic FeII. Upon BH4 binding a polar and salt-bridge interaction network links the three PAH domains, explaining the stability conferred by BH4. Importantly, BH4 binding modulates the interaction between subunits, providing information about PAH allostery. Moreover, we also show that the cryo-EM structure of hPAH in absence of BH4 reveals a highly dynamic conformation for the tetramers. Structural analyses of the hPAH:BH4 subunits revealed that the substrate-induced movement of Tyr138 into the active site could be coupled to the displacement of BH4 from the precatalytic toward the active conformation, a molecular mechanism that was supported by site-directed mutagenesis and targeted molecular dynamics simulations. Finally, comparison of the rat and human PAH structures show that hPAH is more dynamic, which is related to amino acid substitutions that enhance the flexibility of hPAH and may increase the susceptibility to PKU-associated mutations.

scholarly journals Modulating long-range energetics via helix stabilization: A case study using T4 lysozyme

2018 ◽  
Vol 27 (12) ◽  
pp. 2084-2093
Author(s):  
Sabriya N. Rosemond ◽  
Kambiz M. Hamadani ◽  
Jamie H. D. Cate ◽  
Susan Marqusee
Keyword(s):  
Long Range ◽  
T4 Lysozyme

Applications of random graphs

2017 ◽  
Author(s):  
A.C.C. Coolen ◽  
A. Annibale ◽  
E.S. Roberts
Keyword(s):  
Social Networks ◽  
Random Graphs ◽  
Interaction Network ◽  
Power Grids ◽  
Protein Protein Interaction ◽  
Topological Features ◽  
First Case ◽  
The Stability ◽  
Protein Protein Interaction Network

This chapter reviews graph generation techniques in the context of applications. The first case study is power grids, where proposed strategies to prevent blackouts have been tested on tailored random graphs. The second case study is in social networks. Applications of random graphs to social networks are extremely wide ranging – the particular aspect looked at here is modelling the spread of disease on a social network – and how a particular construction based on projecting from a bipartite graph successfully captures some of the clustering observed in real social networks. The third case study is on null models of food webs, discussing the specific constraints relevant to this application, and the topological features which may contribute to the stability of an ecosystem. The final case study is taken from molecular biology, discussing the importance of unbiased graph sampling when considering if motifs are over-represented in a protein–protein interaction network.

Supplier Development at LG Electronics

2020 ◽  
Author(s):  
Hyojin Kim ◽  
Daesik Hur ◽  
Tobias Schoenherr
Keyword(s):  
Management Practice ◽  
Digital Technologies ◽  
Supply Management ◽  
Future Research ◽  
Supplier Development ◽  
Environmentally Conscious ◽  
Competitive Capabilities ◽  
The Stability ◽  
Buyer Firm

Supplier development has been a critical supply management practice since the 1990s. In many instances, it has even become imperative for buyer firms to support and prepare their supply bases for uncertain economic and market environments, socially and environmentally conscious customers, advances in digital technologies, and increasing competition. Yet, research that approaches supplier development with the objective to advance all these dimensions in an integrated fashion is scarce. This study fills this void by exploring how a buyer firm may address these emerging challenges in its supply base. Specifically, an in-depth case study of LG Electronics explores how the firm designs and operates multidimensional supplier development activities to foster the stability and sustainability of its supply base while enhancing its core suppliers’ competitive capabilities. This chapter illustrates how supplier development can be taken to the next level, presents implications for managerial practice, and outlines promising future research avenues.

COMBINING ORAL TRADITIONS AND BAYESIAN CHRONOLOGICAL MODELING TO UNDERSTAND VILLAGE DEVELOPMENT IN THE GULF OF PAPUA (PAPUA NEW GUINEA)

Radiocarbon ◽  
2021 ◽  
pp. 1-21
Author(s):  
Chris Urwin ◽  
Quan Hua ◽  
Henry Arifeae
Keyword(s):  
Papua New Guinea ◽  
New Guinea ◽  
Oral Traditions ◽  
Long Distance ◽  
Spatial History ◽  
The Past ◽  
History Of ◽  
Gulf Of Papua ◽  
The Village

ABSTRACT When European colonists arrived in the late 19th century, large villages dotted the coastline of the Gulf of Papua (southern Papua New Guinea). These central places sustained long-distance exchange and decade-spanning ceremonial cycles. Besides ethnohistoric records, little is known of the villages’ antiquity, spatiality, or development. Here we combine oral traditional and 14C chronological evidence to investigate the spatial history of two ancestral village sites in Orokolo Bay: Popo and Mirimua Mapoe. A Bayesian model composed of 35 14C assays from seven excavations, alongside the oral traditional accounts, demonstrates that people lived at Popo from 765–575 cal BP until 220–40 cal BP, at which time they moved southwards to Mirimua Mapoe. The village of Popo spanned ca. 34 ha and was composed of various estates, each occupied by a different tribe. Through time, the inhabitants of Popo transformed (e.g., expanded, contracted, and shifted) the village to manage social and ceremonial priorities, long-distance exchange opportunities and changing marine environments. Ours is a crucial case study of how oral traditional ways of understanding the past interrelate with the information generated by Bayesian 14C analyses. We conclude by reflecting on the limitations, strengths, and uncertainties inherent to these forms of chronological knowledge.

scholarly journals A Long-Distance Communication Architecture for Medical Devices Based on LoRaWAN Protocol

Electronics ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 940
Author(s):  
Nicoleta Cristina Gaitan
Keyword(s):  
Energy Consumption ◽  
Long Range ◽  
Medical Devices ◽  
Low Energy ◽  
Area Network ◽  
Wide Area Network ◽  
Long Distance ◽  
Communication Architecture ◽  
Low Energy Consumption ◽  
Distance Communication

Recent market studies show that the market for remote monitoring devices of different medical parameters will grow exponentially. Globally, more than 4 million individuals will be monitored remotely from the perspective of different health parameters by 2023. Of particular importance is the way of remote transmission of the information acquired from the medical sensors. At this time, there are several methods such as Bluetooth, WI-FI, or other wireless communication interfaces. Recently, the communication based on LoRa (Long Range) technology has had an explosive development that allows the transmission of information over long distances with low energy consumption. The implementation of the IoT (Internet of Things) applications using LoRa devices based on open Long Range Wide-Area Network (LoRaWAN) protocol for long distances with low energy consumption can also be used in the medical field. Therefore, in this paper, we proposed and developed a long-distance communication architecture for medical devices based on the LoRaWAN protocol that allows data communications over a distance of more than 10 km.

scholarly journals Rational thermostabilisation of four-helix bundle dimeric de novo proteins

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shin Irumagawa ◽  
Kaito Kobayashi ◽  
Yutaka Saito ◽  
Takeshi Miyata ◽  
Mitsuo Umetsu ◽  
...  
Keyword(s):  
Protein Design ◽  
De Novo ◽  
Protein Complexes ◽  
Salt Bridge ◽  
Dynamics Simulation ◽  
Saturation Mutagenesis ◽  
Helix Bundle ◽  
Stable Mutant ◽  
Four Helix Bundle ◽  
The Stability

AbstractThe stability of proteins is an important factor for industrial and medical applications. Improving protein stability is one of the main subjects in protein engineering. In a previous study, we improved the stability of a four-helix bundle dimeric de novo protein (WA20) by five mutations. The stabilised mutant (H26L/G28S/N34L/V71L/E78L, SUWA) showed an extremely high denaturation midpoint temperature (Tm). Although SUWA is a remarkably hyperstable protein, in protein design and engineering, it is an attractive challenge to rationally explore more stable mutants. In this study, we predicted stabilising mutations of WA20 by in silico saturation mutagenesis and molecular dynamics simulation, and experimentally confirmed three stabilising mutations of WA20 (N22A, N22E, and H86K). The stability of a double mutant (N22A/H86K, rationally optimised WA20, ROWA) was greatly improved compared with WA20 (ΔTm = 10.6 °C). The model structures suggested that N22A enhances the stability of the α-helices and N22E and H86K contribute to salt-bridge formation for protein stabilisation. These mutations were also added to SUWA and improved its Tm. Remarkably, the most stable mutant of SUWA (N22E/H86K, rationally optimised SUWA, ROSA) showed the highest Tm (129.0 °C). These new thermostable mutants will be useful as a component of protein nanobuilding blocks to construct supramolecular protein complexes.

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