scholarly journals Chimeric single α-helical domains as rigid fusion protein connections for protein nanotechnology and structural biology

2020 ◽  
Author(s):  
Gabriella Collu ◽  
Tobias Bierig ◽  
Anna-Sophia Krebs ◽  
Sylvain Engilberge ◽  
Niveditha Varma ◽  
...  
Keyword(s):  
Structural Biology ◽  
Building Blocks ◽  
Structural Elements ◽  
Free Standing ◽  
Structural Domains ◽  
Minimal Impact ◽  
Crystal Contacts ◽  
Structural Vaccinology ◽  
Dynamics Simulations ◽  
Crystal Contact

SummaryChimeric fusion proteins are essential tools for protein nanotechnology. Non-optimized protein-protein connections are usually flexible, which makes them unsuitable as structural building blocks. Here we show that the ER/K motif, a single α-helical domain (SAH)1, can be seamlessly fused2 to terminal helices of proteins, forming an extended and partially free-standing rigid helix. Through the intrinsic stability of the SAH, two domains can be connected with a defined distance and orientation. We designed three constructs termed YFPnano, T4Lnano, and MoStoNano, and we show that a single SAH allows the connection of two separate structural domains with sufficient rigidity to form ordered crystals. The analysis of experimentally determined structures and molecular dynamics simulations reveals a certain degree of plasticity in the connections that allows the adaptation to crystal contact opportunities. Our data show that SAHs can be stably integrated into designed structural elements, enabling new possibilities for protein nanotechnology, for example to improve the exposure of epitopes on nanoparticles (structural vaccinology), to engineer crystal contacts with minimal impact in construct flexibility (for the study of protein dynamics), and to design novel biomaterials.

scholarly journals Simulated Breathing: Application of Molecular Dynamics Simulations to Pulmonary Lung Surfactant

Symmetry ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1259
Author(s):  
Maksymilian Dziura ◽  
Basel Mansour ◽  
Mitchell DiPasquale ◽  
P. Charukeshi Chandrasekera ◽  
James W. Gauld ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Pulmonary Surfactant ◽  
Lung Surfactant ◽  
Protein Composition ◽  
Md Simulations ◽  
Building Blocks ◽  
Future Research ◽  
Total Composition ◽  
Protein Components ◽  
Dynamics Simulations

In this review, we delve into the topic of the pulmonary surfactant (PS) system, which is present in the respiratory system. The total composition of the PS has been presented and explored, from the types of cells involved in its synthesis and secretion, down to the specific building blocks used, such as the various lipid and protein components. The lipid and protein composition varies across species and between individuals, but ultimately produces a PS monolayer with the same role. As such, the composition has been investigated for the ways in which it imposes function and confers peculiar biophysical characteristics to the system as a whole. Moreover, a couple of theories/models that are associated with the functions of PS have been addressed. Finally, molecular dynamic (MD) simulations of pulmonary surfactant have been emphasized to not only showcase various group’s findings, but also to demonstrate the validity and importance that MD simulations can have in future research exploring the PS monolayer system.

scholarly journals Dynamic regulation of HIV-1 capsid interaction with the restriction factor TRIM5α identified by magic-angle spinning NMR and molecular dynamics simulations

2018 ◽  
Vol 115 (45) ◽  
pp. 11519-11524 ◽  
Author(s):  
Caitlin M. Quinn ◽  
Mingzhang Wang ◽  
Matthew P. Fritz ◽  
Brent Runge ◽  
Jinwoo Ahn ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Building Blocks ◽  
Magic Angle Spinning ◽  
Magic Angle ◽  
Capsid Assembly ◽  
Dynamic Regulation ◽  
Angle Spinning ◽  
Dynamics Simulations ◽  
Hiv 1

The host factor protein TRIM5α plays an important role in restricting the host range of HIV-1, interfering with the integrity of the HIV-1 capsid. TRIM5 triggers an antiviral innate immune response by functioning as a capsid pattern recognition receptor, although the precise mechanism by which the restriction is imposed is not completely understood. Here we used an integrated magic-angle spinning nuclear magnetic resonance and molecular dynamics simulations approach to characterize, at atomic resolution, the dynamics of the capsid’s hexameric and pentameric building blocks, and the interactions with TRIM5α in the assembled capsid. Our data indicate that assemblies in the presence of the pentameric subunits are more rigid on the microsecond to millisecond timescales than tubes containing only hexamers. This feature may be of key importance for controlling the capsid’s morphology and stability. In addition, we found that TRIM5α binding to capsid induces global rigidification and perturbs key intermolecular interfaces essential for higher-order capsid assembly, with structural and dynamic changes occurring throughout the entire CA polypeptide chain in the assembly, rather than being limited to a specific protein-protein interface. Taken together, our results suggest that TRIM5α uses several mechanisms to destabilize the capsid lattice, ultimately inducing its disassembly. Our findings add to a growing body of work indicating that dynamic allostery plays a pivotal role in capsid assembly and HIV-1 infectivity.

scholarly journals Thermostable designed ankyrin repeat proteins (DARPins) as building blocks for innovative drugs

2021 ◽  
Author(s):  
Johannes Schilling ◽  
Christian Jost ◽  
Ioana Mariuca Ilie ◽  
Joachim Schnabl ◽  
Oralea Buechi ◽  
...  
Keyword(s):  
Melting Temperature ◽  
Building Blocks ◽  
Ankyrin Repeat ◽  
Internal Repeat ◽  
Repeat Proteins ◽  
Repeat Domain ◽  
Ankyrin Repeat Proteins ◽  
Classical Immunoglobulin ◽  
Dynamics Simulations ◽  
Innovative Drugs

AbstractDesigned Ankyrin Repeat Proteins (DARPins) are a class of antibody mimetics with a high and mostly unexplored potential in drug development. They are clinically validated and thus represent a true alternative to classical immunoglobulin formats. In contrast to immunoglobulins, they are built from solenoid protein domains comprising an N-terminal capping repeat, one or more internal repeats and a C-terminal capping repeat. By using in silico analysis and a rationally guided Ala-Scan, we identified position 17 of the N-terminal capping repeat to play a key role for the overall protein thermostability. The melting temperature of a DARPin domain with a single full-consensus internal repeat was increased by about 8°C to 10°C when the original Asp17 was replaced by Leu, Val, Ile, Met, Ala or Thr, as shown by high-temperature unfolding experiments at equilibrium. We then transferred the Asp17Leu mutation to various backgrounds, including different N- and C-terminal capping repeats and clinically validated DARPin domains, such as the VEGF-binding ankyrin repeat domain of abicipar pegol. In all cases, the proteins remained monomeric and showed improvements in the thermostability of about 8°C to 16°C. Thus, the replacement of Asp17 seems to be generically applicable to this drug class. Molecular dynamics simulations show that the Asp17Leu mutation reduces electrostatic repulsion and improves van-der-Waals packing, rendering the DARPin domain less flexible and more stable. Interestingly, such a beneficial Asp17Leu mutation is present in the N-terminal caps of three of the five DARPin domains of ensovibep, a SARS-CoV-2 entry inhibitor currently in clinical development. This mutation is likely responsible, at least in part, for the very high melting temperature (>90°C) of this promising anti-Covid-19 drug. Overall, such N-terminal capping repeats with increased thermostability seem to be beneficial for the development of innovative drugs based on DARPins.

scholarly journals WAVE ANALYSIS OF A L-BEAM STRUCTURE WITH A BLOCKING MASS

2020 ◽  
Author(s):  
Johnny Tiu ◽  
Richard Bachoo
Keyword(s):  
Systematic Approach ◽  
Building Blocks ◽  
Element Model ◽  
Structural Systems ◽  
Structural Elements ◽  
Wave Analysis ◽  
Beam Structure ◽  
Reflection Matrix ◽  
Geometric Changes ◽  
Transmission And Reflection

The wave vibration approach regards the vibrations present within a structure as waves, whereby each wave flows along a structural member and upon meeting a discontinuity; portions of the incident wave are reflected and transmitted across the discontinuity. The reflected, transmitted and propagating wave transformations are represented mathematically by matrices, which are used to develop a set of wave relation equations at each discontinuity that can be used to describe the frequency response of the system holistically. This method creates a systematic approach of analysing structures by utilizing common cases as building blocks for a specific structure. The L-joint, described as two beams meeting at right angles; is a ubiquitous case for spatial portal and structural frames, which may become geometrically complex. Such structures are well suited to a wave vibration approach due to the large number of geometric changes and the prevalence as well as recurrence of specific cases. In this paper, the L-joint expanded to include a blocking mass, typically employed in structural systems and allows for the isolation and reflection of vibration away from contiguous structural elements. Included are; variance of transmission and reflection matrix components as the size of the blocking mass increases, numerical examples and comparison to a Finite Element Model developed in ANSYS.

scholarly journals Design, Characterization and Molecular Modeling of New Fluorinated Paramagnetic Contrast Agents for Dual 1H/19F MRI

2020 ◽  
Vol 6 (1) ◽  
pp. 8 ◽  
Author(s):  
Emilie Hequet ◽  
Céline Henoumont ◽  
Vera Djouana Kenfack ◽  
Vincent Lemaur ◽  
Roberto Lazzaroni ◽  
...  
Keyword(s):  
Contrast Agents ◽  
3D Structure ◽  
Relaxation Times ◽  
Cycloaddition Reaction ◽  
Building Blocks ◽  
Lanthanide Ion ◽  
19F Mri ◽  
Fluorine Magnetic Resonance Imaging ◽  
Magnetic Resonance Imaging Mri ◽  
Dynamics Simulations

One major goal in medical imaging is the elaboration of more efficient contrast agents (CAs). Those agents need to be optimized for the detection of affected tissues such as cancers or tumors while decreasing the injected quantity of agents. The paramagnetic contrast agents containing fluorine atoms can be used for both proton and fluorine magnetic resonance imaging (MRI), and they open the possibility of simultaneously mapping the anatomy using 1H MRI and accurately locating the agents using 19F MRI. One of the challenges in this domain is to synthesize molecules containing several chemically equivalent fluorine atoms with relatively short relaxation times to allow the recording of 19F MR images in good conditions. With that aim, we propose to prepare a CA containing a paramagnetic center and nine chemically equivalent fluorine atoms using a cycloaddition reaction between two building blocks. These fluorinated contrast agents are characterized by 19F NMR, showing differences in the fluorine relaxation times T1 and T2 depending on the lanthanide ion. To complement the experimental results, molecular dynamics simulations are performed to shed light on the 3D-structure of the molecules in order to estimate the distance between the lanthanide ion and the fluorine atoms.

scholarly journals Interface Characteristics of Neat Melts and Binary Mixtures of Polyethylenes from Atomistic Molecular Dynamics Simulations

Polymers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1059
Author(s):  
Sanghun Lee ◽  
Curtis W. Frank ◽  
Do Y. Yoon
Keyword(s):  
Molecular Dynamics ◽  
Surface Tension ◽  
Molecular Dynamics Simulations ◽  
Binary Mixtures ◽  
Surface Segregation ◽  
Surface Region ◽  
Polymer Chains ◽  
Methyl Groups ◽  
Free Standing ◽  
Dynamics Simulations

Molecular dynamics simulations of free-standing thin films of neat melts of polyethylene (PE) chains up to C150H302 and their binary mixtures with n-C13H28 are performed employing a united atom model. We estimate the surface tension values of PE melts from the atomic virial tensor over a range of temperatures, which are in good agreement with experimental results. Compared with short n-alkane systems, there is an enhanced surface segregation of methyl chain ends in longer PE chains. Moreover, the methyl groups become more segregated in the surface region with decreasing temperature, leading to the conclusion that the surface-segregation of methyl chain ends mainly arises from the enthalpic origin attributed to the lower cohesive energy density of terminal methyl groups. In the mixtures of two different chain lengths, the shorter chains are more likely to be found in the surface region, and this molecular segregation in moderately asymmetric mixtures in the chain length (C13H28 + C44H90) is dominated by the enthalpic effect of methyl chain ends. Such molecular segregation is further enhanced and dominated by the entropic effect of conformational constraints in the surface for the highly asymmetric mixtures containing long polymer chains (C13H28 + C150H3020). The estimated surface tension values of the mixtures are consistent with the observed molecular segregation characteristics. Despite this molecular segregation, the normalized density of methyl chain ends of the longer chain is more strongly enhanced, as compared with the all-segment density of the longer chain itself, in the surface region of melt mixtures. In addition, the molecular segregation results in higher order parameter of the shorter-chain segments at the surface and deeper persistence of surface-induced segmental order into the film for the longer chains, as compared with those in neat melt films.

Atomic Dynamics in Complex Metallic Alloys

2013 ◽  
Vol 1517 ◽  
Author(s):  
Holger Euchner ◽  
Stephane Pailhès ◽  
Tsunetomo Yamada ◽  
Ryuji Tamura ◽  
Tsutomu Ishimasa ◽  
...  
Keyword(s):  
Lattice Dynamics ◽  
Structural Complexity ◽  
Building Blocks ◽  
Metallic Alloys ◽  
Strong Reduction ◽  
Large Numbers ◽  
Unit Cells ◽  
Dynamics Simulations ◽  
The Impact ◽  
Complex Metallic Alloys

ABSTRACTComplex Metallic Alloys (CMAs) are metallic solids of high structural complexity, consisting of large numbers of atoms in their unit cells. Consequences of this structural complexity are manifold and give rise to a variety of exciting physical properties. The impact that such structural complexity may have on the lattice dynamics will be discussed. The surprising dynamical flexibility of Tsai-type clusters with the symmetry breaking central tetrahedron will be addressed for Zn6Sc, while in the Ba-Ge-Ni clathrate system the dynamics of encaged Ba guest atoms in the surrounding Ge-Ni host framework is analysed with respect to the experimentally evidenced strong reduction of lattice thermal conductivity. For both systems experimental results from neutron scattering are analyzed and interpreted on atomistic scale by means of ab initio and molecular dynamics simulations, resulting in a picture with the respective structural building blocks as the origin of the peculiarities in the dynamics.

Metalloligand Strategies for Assembling Heteronuclear Nanocages – Recent Developments

2019 ◽  
Vol 72 (10) ◽  
pp. 731 ◽  
Author(s):  
Feng Li ◽  
Leonard F. Lindoy
Keyword(s):  
Structural Properties ◽  
Metal Ion ◽  
Rational Design ◽  
Building Blocks ◽  
Structural Elements ◽  
Present Discussion ◽  
The Past ◽  
Recent Developments ◽  
Metal Organic ◽  
Multifunctional Ligand

The use of metalloligands as building blocks for the assembly of metallo-organic cages has received increasing attention over the past two decades or so. In part, the popularity of this approach reflects its stepwise nature that lends itself to the predesigned construction of metallocages and especially heteronuclear metallocages. The focus of the present discussion is on the use of metalloligands for the construction of discrete polyhedral cages, very often incorporating heterometal ions as structural elements. The metalloligand approach uses metal-bound multifunctional ligand building blocks that display predesigned structural properties for coordination to a second metal ion such that the rational design and construction of both homo- and heteronuclear metal–organic cages are facilitated. The present review covers published literature in the area from early 2015 to early 2019.

scholarly journals Self-standing and flexible covalent organic framework (COF) membranes for molecular separation

2020 ◽  
Vol 6 (41) ◽  
pp. eabb1110
Author(s):  
Jiangtao Liu ◽  
Gang Han ◽  
Dieling Zhao ◽  
Kangjia Lu ◽  
Jie Gao ◽  
...  
Keyword(s):  
Building Blocks ◽  
Shape Selectivity ◽  
Honeycomb Lattice ◽  
Free Standing ◽  
Covalent Bonds ◽  
Separation Science ◽  
Covalent Organic Framework ◽  
Molecular Building Blocks ◽  
Almost All ◽  
Organic Framework

Almost all covalent organic framework (COF) materials conventionally fabricated by solvothermal method at high temperatures and pressures are insoluble and unprocessable powders, which severely hinder their widespread applications. This work develops an effective and facile strategy to construct flexible and free-standing pure COF membranes via the liquid-liquid interface-confined reaction at room temperature and atmospheric pressure. The aperture size and channel chemistry of COF membranes can be rationally designed by bridging various molecular building blocks via strong covalent bonds. Benefiting from the highly-ordered honeycomb lattice, high solvent permeances are successfully obtained and follow the trend of acetonitrile > acetone > methanol > ethanol > isopropanol. Interestingly, the imine-linked COF membrane shows higher nonpolar solvent permeances than b-ketoenamine-linked COF due to their difference in pore polarity. Both kinds of COF membranes exhibit high solvent permeances, precise molecular sieving, excellent shape selectivity, and sufficient flexibility for membrane-based separation science and technology.

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