Predicting large-scale conformational changes in proteins using energy-weighted normal modes

Abstract Observations made by the Sounding of the Atmosphere using Broadband Emission Radiometry (SABER) instrument on board NASA’s Thermosphere–Ionosphere–Mesosphere Energetics and Dynamics (TIMED) satellite have been processed using Salby’s fast Fourier synoptic mapping (FFSM) algorithm. The mapped data provide a first synoptic look at the mean structure and traveling waves of the mesosphere and lower thermosphere (MLT) since the launch of the TIMED satellite in December 2001. The results show the presence of various wave modes in the MLT, which reach largest amplitude above the mesopause and include Kelvin and Rossby–gravity waves, eastward-propagating diurnal oscillations (“non-sun-synchronous tides”), and a set of quasi-normal modes associated with the so-called 2-day wave. The latter exhibits marked seasonal variability, attaining large amplitudes during the solstices and all but disappearing at the equinoxes. SABER data also show a strong quasi-stationary Rossby wave signal throughout the middle atmosphere of the winter hemisphere; the signal extends into the Tropics and even into the summer hemisphere in the MLT, suggesting ducting by westerly background zonal winds. At certain times of the year, the 5-day Rossby normal mode and the 4-day wave associated with instability of the polar night jet are also prominent in SABER data.

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Metastable Intermediates as Stepping Stones on the Maturation Pathways of Viral Capsids

mBio ◽

10.1128/mbio.02067-14 ◽

2014 ◽

Vol 5 (6) ◽

Cited By ~ 10

Author(s):

Giovanni Cardone ◽

Robert L. Duda ◽

Naiqian Cheng ◽

Lili You ◽

James F. Conway ◽

...

Keyword(s):

Conformational Changes ◽

Large Scale ◽

Structural Changes ◽

Energy Landscape ◽

Potential Hazard ◽

Stepping Stones ◽

Scanning Calorimetry ◽

Conformational Effects ◽

Capsid Maturation ◽

Capsid Integrity

ABSTRACT As they mature, many capsids undergo massive conformational changes that transform their stability, reactivity, and capacity for DNA. In some cases, maturation proceeds via one or more intermediate states. These structures represent local minima in a rich energy landscape that combines contributions from subunit folding, association of subunits into capsomers, and intercapsomer interactions. We have used scanning calorimetry and cryo-electron microscopy to explore the range of capsid conformations accessible to bacteriophage HK97. To separate conformational effects from those associated with covalent cross-linking (a stabilization mechanism of HK97), a cross-link-incompetent mutant was used. The mature capsid Head I undergoes an endothermic phase transition at 60°C in which it shrinks by 7%, primarily through changes in its hexamer conformation. The transition is reversible, with a half-life of ~3 min; however, >50% of reverted capsids are severely distorted or ruptured. This observation implies that such damage is a potential hazard of large-scale structural changes such as those involved in maturation. Assuming that the risk is lower for smaller changes, this suggests a rationalization for the existence of metastable intermediates: that they serve as stepping stones that preserve capsid integrity as it switches between the radically different conformations of its precursor and mature states. IMPORTANCE Large-scale conformational changes are widespread in virus maturation and infection processes. These changes are accompanied by the release of conformational free energy as the virion (or fusogenic glycoprotein) switches from a precursor state to its mature state. Each state corresponds to a local minimum in an energy landscape. The conformational changes in capsid maturation are so radical that the question arises of how maturing capsids avoid being torn apart. Offering proof of principle, severe damage is inflicted when a bacteriophage HK97 capsid reverts from the (nonphysiological) state that it enters when heated past 60°C. We suggest that capsid proteins have been selected in part by the criterion of being able to avoid sustaining collateral damage as they mature. One way of achieving this—as with the HK97 capsid—involves breaking the overall transition down into several smaller steps in which the risk of damage is reduced.

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Nuclear pores constrict upon energy depletion

10.1101/2020.07.30.228585 ◽

2020 ◽

Author(s):

Christian E Zimmerli ◽

Matteo Allegretti ◽

Vasileios Rantos ◽

Sara K Goetz ◽

Agnieszka Obarska-Kosinska ◽

...

Keyword(s):

Conformational Changes ◽

Large Scale ◽

Electron Tomography ◽

Nuclear Pore ◽

Nuclear Pore Complexes ◽

Energy Status ◽

Energy Depletion ◽

Time Variations ◽

Subtomogram Averaging ◽

Pore Complexes

Nuclear pore complexes (NPCs) fuse the inner and outer nuclear membranes and mediate nucleocytoplasmic exchange. They are made of 30 different nucleoporins that form an intricate cylindrical architecture around an aqueous central channel. This architecture is highly dynamic in space and time. Variations in NPC diameter were reported, but the physiological circumstances and the molecular details remain unknown. Here we combined cryo-electron tomography and subtomogram averaging with integrative structural modeling to capture a molecular movie of the respective large-scale conformational changes in cellulo. While actively transporting NPCs adopt a dilated conformation, they strongly constrict upon cellular energy depletion. Fluorescence recovery after photo bleaching experiments show that NPC constriction is concomitant with reduced diffusion and active transport across the nuclear envelope. Our data point to a model where the energy status of cells is linked to the conformation of NPC architecture.

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Structural insights into the activation of human calcium-sensing receptor

10.1101/2021.03.30.437720 ◽

2021 ◽

Author(s):

Xiaochen Chen ◽

Lu Wang ◽

Zhanyu Ding ◽

Qianqian Cui ◽

Li Han ◽

...

Keyword(s):

Conformational Changes ◽

Large Scale ◽

Transmembrane Domains ◽

Structural Basis ◽

Calcium Sensing Receptor ◽

Calcium Sensing ◽

Cryo Electron Microscopy ◽

Activation Mechanisms ◽

G Protein Coupled ◽

Structural Insights

AbstractHuman calcium-sensing receptor (CaSR) is a G-protein-coupled receptor that maintains Ca2+ homeostasis in serum. Here, we present the cryo-electron microscopy structures of the CaSR in the inactive and active states. Complemented with previously reported crystal structures of CaSR extracellular domains, it suggests that there are three distinct conformations: inactive, intermediate and active state during the activation. We used a negative allosteric nanobody to stabilize the CaSR in the fully inactive state and found a new binding site for Ca2+ ion that acts as a composite agonist with L-amino acid to stabilize the closure of active Venus flytraps. Our data shows that the agonist binding leads to the compaction of the dimer, the proximity of the cysteine-rich domains, the large-scale transitions of 7-transmembrane domains, and the inter-and intrasubunit conformational changes of 7-transmembrane domains to accommodate the downstream transducers. Our results reveal the structural basis for activation mechanisms of the CaSR.

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Antigen Presentation of mRNA-Based and Virus-Vectored SARS-CoV-2 Vaccines

Vaccines ◽

10.3390/vaccines9080848 ◽

2021 ◽

Vol 9 (8) ◽

pp. 848

Author(s):

Ger T. Rijkers ◽

Nynke Weterings ◽

Andres Obregon-Henao ◽

Michaëla Lepolder ◽

Taru S. Dutt ◽

...

Keyword(s):

Antigen Presentation ◽

Conformational Changes ◽

Dna Sequences ◽

Neutralizing Antibodies ◽

Large Scale ◽

Viral Vector ◽

Adenovirus Vector ◽

Platelet Factor ◽

Immune Mediated ◽

Protein Encoding

Infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes Coronavirus Disease 2019 (COVID-19), which has reached pandemic proportions. A number of effective vaccines have been produced, including mRNA vaccines and viral vector vaccines, which are now being implemented on a large scale in order to control the pandemic. The mRNA vaccines are composed of viral Spike S1 protein encoding mRNA incorporated in a lipid nanoparticle and stabilized by polyethylene glycol (PEG). The mRNA vaccines are novel in many respects, including cellular uptake and the intracellular routing, processing, and secretion of the viral protein. Viral vector vaccines have incorporated DNA sequences, encoding the SARS-CoV-2 Spike protein into (attenuated) adenoviruses. The antigen presentation routes in MHC class I and class II, in relation to the induction of virus-neutralizing antibodies and cytotoxic T-lymphocytes, will be reviewed. In rare cases, mRNA vaccines induce unwanted immune mediated side effects. The mRNA-based vaccines may lead to an anaphylactic reaction. This reaction may be triggered by PEG. The intracellular routing of PEG and potential presentation in the context of CD1 will be discussed. Adenovirus vector-based vaccines have been associated with thrombocytopenic thrombosis events. The anti-platelet factor 4 antibodies found in these patients could be generated due to conformational changes of relevant epitopes presented to the immune system.

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Simplified geometric representations of protein structures identify complementary interaction interfaces

10.1101/2019.12.18.880575 ◽

2019 ◽

Cited By ~ 1

Author(s):

Caitlyn L. McCafferty ◽

Edward M. Marcotte ◽

David W. Taylor

Keyword(s):

Conformational Changes ◽

Protein Interaction ◽

Protein Function ◽

Large Scale ◽

Predictive Accuracy ◽

Protein Complexes ◽

Protein Structures ◽

Molecular Properties ◽

3D Structures ◽

Geometric Representations

ABSTRACTProtein-protein interactions are critical to protein function, but three-dimensional (3D) arrangements of interacting proteins have proven hard to predict, even given the identities and 3D structures of the interacting partners. Specifically, identifying the relevant pairwise interaction surfaces remains difficult, often relying on shape complementarity with molecular docking while accounting for molecular motions to optimize rigid 3D translations and rotations. However, such approaches can be computationally expensive, and faster, less accurate approximations may prove useful for large-scale prediction and assembly of 3D structures of multi-protein complexes. We asked if a reduced representation of protein geometry retains enough information about molecular properties to predict pairwise protein interaction interfaces that are tolerant of limited structural rearrangements. Here, we describe a cuboid transformation of 3D protein accessible surfaces on which molecular properties such as charge, hydrophobicity, and mutation rate can be easily mapped, implemented in the MorphProt package. Pairs of surfaces are compared to rapidly assess partner-specific potential surface complementarity. On two available benchmarks of 85 overall known protein complexes, we observed F1 scores (a weighted combination of precision and recall) of 19-34% at correctly identifying protein interaction surfaces, comparable to more computationally intensive 3D docking methods in the annual Critical Assessment of PRedicted Interactions. Furthermore, we examined the effect of molecular motion through normal mode simulation on a benchmark receptor-ligand pair and observed no marked loss of predictive accuracy for distortions of up to 6 Å RMSD. Thus, a cuboid transformation of protein surfaces retains considerable information about surface complementarity, offers enhanced speed of comparison relative to more complex geometric representations, and exhibits tolerance to conformational changes.

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Reverberation Intensity Decaying in Range-Dependent Waveguide

Journal of Theoretical and Computational Acoustics ◽

10.1142/s2591728519500075 ◽

2019 ◽

Vol 27 (03) ◽

pp. 1950007

Author(s):

J. R. Wu ◽

T. F. Gao ◽

E. C. Shang

Keyword(s):

Large Scale ◽

Back Propagation ◽

Normal Modes ◽

Small Scale ◽

Signal Pulse ◽

First Order ◽

Orthogonal Property ◽

Short Signal ◽

Scale Roughness ◽

Special Case

In this paper, an analytic range-independent reverberation model based on the first-order perturbation theory is extended to range-dependent waveguide. This model considers the effect of bottom composite roughness: small-scale bottom rough surface provides dominating energy for reverberation, whereas large-scale roughness has the effect of forward and back propagation. For slowly varying bottom and short signal pulse, analytic small-scale roughness backscattering theory is adapted in range-dependent waveguides. A parabolic equation is used to calculate Green functions in range-dependent waveguides, and the orthogonal property of local normal modes is employed to estimate the modal spectrum of PE field. Synthetic tests demonstrate that the proposed reverberation model works well, and it can also predict the reverberation of range-independent waveguide as a special case.

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Molybdate pumping into the molybdenum storage protein via an ATP-powered piercing mechanism

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1913031116 ◽

2019 ◽

Vol 116 (52) ◽

pp. 26497-26504 ◽

Cited By ~ 2

Author(s):

Steffen Brünle ◽

Martin L. Eisinger ◽

Juliane Poppe ◽

Deryck J. Mills ◽

Julian D. Langer ◽

...

Keyword(s):

Conformational Changes ◽

Storage Protein ◽

Large Scale ◽

Azotobacter Vinelandii ◽

Current Data ◽

Nucleophilic Attack ◽

Valuable Insight ◽

Similar Reaction ◽

Α Subunit ◽

Ump Kinase

The molybdenum storage protein (MoSto) deposits large amounts of molybdenum as polyoxomolybdate clusters in a heterohexameric (αβ)3cage-like protein complex under ATP consumption. Here, we suggest a unique mechanism for the ATP-powered molybdate pumping process based on X-ray crystallography, cryoelectron microscopy, hydrogen-deuterium exchange mass spectrometry, and mutational studies of MoSto fromAzotobacter vinelandii. First, we show that molybdate, ATP, and Mg2+consecutively bind into the open ATP-binding groove of the β-subunit, which thereafter becomes tightly locked by fixing the previously disordered N-terminal arm of the α-subunit over the β-ATP. Next, we propose a nucleophilic attack of molybdate onto the γ-phosphate of β-ATP, analogous to the similar reaction of the structurally related UMP kinase. The formed instable phosphoric-molybdic anhydride becomes immediately hydrolyzed and, according to the current data, the released and accelerated molybdate is pressed through the cage wall, presumably by turning aside the Metβ149 side chain. A structural comparison between MoSto and UMP kinase provides valuable insight into how an enzyme is converted into a molecular machine during evolution. The postulated direct conversion of chemical energy into kinetic energy via an activating molybdate kinase and an exothermic pyrophosphatase reaction to overcome a proteinous barrier represents a novelty in ATP-fueled biochemistry, because normally, ATP hydrolysis initiates large-scale conformational changes to drive a distant process.

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On Spectral Analysis of Mesoscale Eddies. Part I: Linear Analysis

Journal of Physical Oceanography ◽

10.1175/jpo-d-12-0232.1 ◽

2013 ◽

Vol 43 (12) ◽

pp. 2505-2527 ◽

Cited By ~ 24

Author(s):

P. Berloff ◽

I. Kamenkovich

Keyword(s):

Reynolds Number ◽

Spectral Analysis ◽

Large Scale ◽

Normal Modes ◽

Mesoscale Eddies ◽

Linear Analysis ◽

Vertical Shear ◽

Systematic Analysis ◽

Linear Dynamics ◽

Zonal Jets

Abstract This study aims to understand the ocean’s circulation, which is characterized by the presence of multiple alternating zonal jets and transient mesoscale eddies, by systematic analysis of the underlying linear dynamics of this system. For this purpose, properties of the linear normal modes such as growth rates, dispersion, spatial structure, and nonlinear self-interactions are explored for a hierarchy of idealized, vertically, and horizontally sheared flows with increasing complexity. The authors find that large-scale background vertical shear, alternating multiple zonal jets, bottom friction, and the Reynolds number have important effects on these modes. This study hypothesizes that when these effects are taken into account, the linear results can be used to predict many properties of nonlinear mesoscale eddies. This hypothesis is confirmed in Part II of this paper.

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