Biophysical Journal

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ISSN / EISSN : 0006-3495 / 1542-0086
Published by: Elsevier BV (10.1016)
Total articles ≅ 68,025
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Shigenori Nagatomo, Teizo Kitagawa, Masako Nagai
Published: 1 July 2021
Biophysical Journal, Volume 120, pp 2734-2745; doi:10.1016/j.bpj.2021.05.014

Using various mutants, we investigated to date the roles of the Fe-histidine (F8) bonds in cooperative O2 binding of human hemoglobin (Hb) and differences in roles between α and β subunits in the α2β2 tetramer. An Hb variant with a mutation in the heme cavity exhibited an unexpected feature. When the β mutant rHb (βH92G), in which the proximal histidine (His F8) of the β subunit is replaced by glycine (Gly), was subjected to ion exchange chromatography (Q Sepharose column) and eluted with an NaCl concentration gradient in the presence of imidazole, yielded two large peaks, while the corresponding α mutant, rHb (αH87G), gave a single peak similar to Hb A. The β mutant rHb proteins under each peak had identical isoelectric points (pI) according to isoelectric focusing electrophoresis. Proteins under each peak were further characterized by Sephadex G-75 gel filtration, far-UV CD, 1H NMR, and resonance Raman spectroscopy. We found that rHb (βH92G) exists as a mixture of αβ dimers and α2β2 tetramers, and that hemes are released from β subunits in a fraction of the dimers. An approximate amount of released hemes were estimated to be as large as 30% with Raman relative intensities. It is stressed that Q Sepharose columns can distinguish differences in structural flexibility of proteins having identical pIs by altering the exit rates from the porous beads. Thus, the role of Fe-His (F8) bonds in stabilizing the Hb tetramer first described by Barrick et al. was confirmed in the present study. In addition, it was found in this study that a specific Fe-His bond in the β subunit minimizes globin structural flexibility.
Natalia Ostrowska, Michael Feig, Joanna Trylska
Published: 1 July 2021
Biophysical Journal; doi:10.1016/j.bpj.2021.07.008

Nestor Lopez Mora, Heather E. Findlay, Nicholas J. Brooks, Sowmya Purushothaman, Oscar Ces, Paula J. Booth.
Published: 1 July 2021
Biophysical Journal; doi:10.1016/j.bpj.2021.06.038

Benjamin Fröhlich, Anil K. Dasanna, Christine Lansche, Julian Czajor, Cecilia P. Sanchez, Marek Cyrklaff, Akihisa Yamamoto, Alister Craig, Ulrich S. Schwarz, Michael Lanzer, et al.
Published: 1 July 2021
Biophysical Journal; doi:10.1016/j.bpj.2021.07.003

Agnieszka Obarska-Kosinska, Benedikt Rennekamp, Aysecan Ünal,
Published: 1 July 2021
Biophysical Journal; doi:10.1016/j.bpj.2021.07.009

Type I collagen is the main structural component of many tissues in the human body. It provides excellent mechanical properties to connective tissue and acts as a protein interaction hub. There is thus a wide interest in understanding the properties and diverse functions of type I collagen at the molecular level. A precondition is an atomistic collagen I structure as it occurs in native tissue. To this end, we built full-atom models of crosslinked collagen fibrils by integrating the low-resolution structure of collagen fibril available from X-ray fiber diffraction with high-resolution structures of short collagen-like peptides from X-ray crystallography and mass spectrometry data. We created a web resource of collagen models for 20 different species with a large variety of crosslink types and localization within the fibril, to facilitate structure-based analyses and simulations of type I collagen in health and disease. To easily enable simulations, we provide parameters of the modeled crosslinks for an Amber force field. The repository of collagen models is available at
Pei Liu, , M. Carme Calderer, , Mariel Vazquez, Shawn Walker
Published: 1 July 2021
Biophysical Journal; doi:10.1016/j.bpj.2021.07.006

Bacteriophages densely pack their long dsDNA genome inside a protein capsid. The conformation of the viral genome inside the capsid is consistent with a hexagonal liquid crystalline structure. Experiments have confirmed that the details of the hexagonal packing depend on the electrochemistry of the capsid and its environment. In this work, we propose a biophysical model that quantifies the relationship between DNA configurations inside bacteriophage capsids and the types and concentrations of ions present in a biological system. We introduce an expression for the free energy which combines the electrostatic energy with contributions from bending of individual segments of DNA and Lennard–Jones-type interactions between these segments. The equilibrium points of this energy solve a partial differential equation that defines the distributions of DNA and the ions inside the capsid. We develop a computational approach that allows us to simulate much larger systems than what is possible using the existing molecular-level methods. In particular, we are able to estimate bending and repulsion between the DNA segments as well as the full electrochemistry of the solution, both inside and outside of the capsid. The numerical results show good agreement with existing experiments and with molecular dynamics simulations for small capsids.
Savvas Polydorides, Georgios Archontis
Published: 1 July 2021
Biophysical Journal, Volume 120, pp 2859-2871; doi:10.1016/j.bpj.2021.02.049

The coronavirus SARS-CoV-2, that is responsible for the COVID-19 pandemic, and the closely related SARS-CoV coronavirus enter cells by binding at the human angiotensin converting enzyme 2 (hACE2). The stronger hACE2 affinity of SARS-CoV-2 has been connected with its higher infectivity. In this work, we study hACE2 complexes with the receptor binding domains (RBDs) of the human SARS-CoV-2 and human SARS-CoV viruses, using all-atom molecular dynamics (MD) simulations and Computational Protein Design (CPD) with a physics-based energy function. The MD simulations identify charge-modifying substitutions between the CoV-2 and CoV RBDs, which either increase or decrease the hACE2 affinity of the SARS-CoV-2 RBD. The combined effect of these mutations is small, and the relative affinity is mainly determined by substitutions at residues in contact with hACE2. Many of these findings are in line and interpret recent experiments. Our CPD calculations redesign positions 455, 493, 494 and 501 of the SARS-CoV-2 RBM, which contact hACE2 in the complex and are important for ACE2 recognition. Sampling is enhanced by an adaptive importance sampling Monte Carlo method. Sequences with increased affinity replace CoV-2 glutamine by a negative residue at position 493, serine by nonpolar, aromatic or a threonine at position 494, and asparagine by valine or threonine at position 501. Substitutions at positions 455 and 501 have a smaller effect on affinity. Substitutions suggested by our design are seen in viral sequences encountered in other species, including bat and pangolin. Our results might be used to identify potential virus strains with higher human infectivity and assist in the design of peptide-based or peptidomimetic compounds with the potential to inhibit SARS-CoV-2 binding at hACE2.
, Sean J. Williams, Jessica M. Banks, Wong H. Hui, Z. Hong Zhou, Lin Jin
Published: 1 July 2021
Biophysical Journal, Volume 120, pp 2766-2770; doi:10.1016/j.bpj.2021.03.012

Understanding the structure of messenger RNA (mRNA) lipid nanoparticles, and specifically the microenvironment of the mRNA molecules within these entities, is fundamental to advancing their biomedical potential. Here, we show that a permeating cationic dye, thionine, can serve as a cryogenic electron microscopy contrasting agent by binding selectively to encapsulated mRNA without disturbing lipid nanoparticle morphology. Cryo-electron microscopy images identify the mRNA location, revealing that mRNA may exist within solvent-filled cavities or may be substantially lipid associated.
Maximilia F. de Souza Degenhardt, Phelipe A.M. Vitale, Layara A. Abiko, Martin Zacharias, Michael Sattler, Cristiano L.P. Oliveira,
Published: 1 July 2021
Biophysical Journal; doi:10.1016/j.bpj.2021.07.022

Na+/Ca2+ exchangers (NCX) are secondary active transporters that couple the translocation of Na+ with the transport of Ca2+ in the opposite direction. The exchanger is an essential Ca2+ extrusion mechanism in excitable cells. It consists of a transmembrane domain and a large intracellular loop that contains two Ca2+-binding domains, CBD1 and CBD2. The two CBDs are adjacent to each other and form a two-domain Ca2+-sensor called CBD12. Binding of intracellular Ca2+ to CBD12 activates the NCX but inhibits the Na+/Ca2+ exchanger of Drosophila, CALX. NMR spectroscopy and SAXS studies showed that CALX and NCX CBD12 constructs display significant inter-domain flexibility in the Apo state, but assume rigid inter-domain arrangements in the Ca2+-bound state. However, detailed structure information on CBD12 in the Apo state is missing. Structural characterization of proteins formed by two or more domains connected by flexible linkers is notoriously challenging and requires the combination of orthogonal information from multiple sources. As an attempt to characterize the conformational ensemble of CALX-CBD12 in the Apo state, we applied molecular dynamics (MD) simulations, NMR (1H-15N RDCs) and Small-Angle X-Ray Scattering (SAXS) data in a combined strategy to select an ensemble of conformations in agreement with the experimental data. This joint approach demonstrated that CALX-CBD12 preferentially samples closed conformations, while the wide-open inter-domain arrangement characteristic of the Ca2+-bound state is less frequently sampled. These results are consistent with the view that Ca2+ binding shifts the CBD12 conformational ensemble towards extended conformers, which could be a key step in the Na+/Ca2+ exchangers' allosteric regulation mechanism. The present strategy, combining MD with NMR and SAXS, provides a powerful approach to select ensembles of conformations, which could be applied to other flexible multi-domain systems.
Ning Liu, Poorya Chavoshnejad, Shaoheng Li, Mir Jalil Razavi, Tianming Liu, Ramana Pidaparti,
Published: 1 July 2021
Biophysical Journal; doi:10.1016/j.bpj.2021.07.019

Axons bundles cross-linked by microtubule (MT) associate proteins (MAP) and bounded by a shell skeleton are critical for normal function of neurons. Understanding effects of the complexly geometrical parameters on their mechanical properties can help gain a biomechanical perspective on the neurological functions of axons and thus brain disorders caused by the structural failure of axons. Here, the tensile mechanical properties of MT bundles cross-linked by tau proteins are investigated by systematically tuning MT length, axonal cross-section radius, and tau protein spacing in a bead-spring coarse-grained model. Our results indicate that the stress-strain curves of axons can be divided into two regimes, a nonlinear elastic regime dominated by rigid-body like inter-MT sliding, and a linear elastic regime dominated by affine deformation of both tau proteins and MTs. From the energetic analyses, first, the tau proteins dominate the mechanical performance of axons under tension. In the nonlinear regime, tau proteins undergo a rigid-body like rotating motion rather than elongating, while in the nonlinear elastic regime, tau proteins undergo a flexible elongating deformation along the MT axis. Second, as the average spacing between adjacent tau proteins along the MT axial direction increases from 25 nm to 125 nm, the Young's modulus of axon experiences a linear decrease while with the average space varying from 125 nm to 175 nm, and later reaches a plateau value with a stable fluctuation. Third, the increment of the cross-section radius of the MT bundle leads to a decrease in Young's modulus of axon, which is possibly attributed to the decrease in MT numbers per cross section. Overall, our research findings offer a new perspective into understanding the effects of geometrical parameters on the mechanics of MT bundles as well as serving as a theoretical basis for the development of artificial MT complexes potentially towards medical applications.
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