Elastic versus Brittle Mechanical Responses Predicted for Dimeric Cadherin Complexes

Cadherins are a superfamily of adhesion proteins involved in a variety of biological processes that include the formation of intercellular contacts, the maintenance of tissue integrity, and the development of neuronal circuits. These transmembrane proteins are characterized by ectodomains composed of a variable number of extracellular cadherin (EC) repeats that are similar but not identical in sequence and fold. E-cadherin, along with desmoglein and desmocollin proteins, are three classical-type cadherins that have slightly curved ectodomains and engage in homophilic and heterophilic interactions through an exchange of conserved tryptophan residues in their N-terminal EC1 repeat. In contrast, clustered protocadherins are straighter than classical cadherins and interact through an antiparallel homophilic binding interface that involves overlapped EC1 to EC4 repeats. Here we present molecular dynamics simulations that model the adhesive domains of these cadherins using available crystal structures, with systems encompassing up to 2.8 million atoms. Simulations of complete classical cadherin ectodomain dimers predict a two-phased elastic response to force in which these complexes first softly unbend and then stiffen to unbind without unfolding. Simulated α, β, and γ clustered protocadherin homodimers lack a two-phased elastic response, are brittle and stiffer than classical cadherins, and exhibit complex unbinding pathways that in some cases involve transient intermediates. We propose that these distinct mechanical responses are important for function, with classical cadherin ectodomains acting as molecular shock absorbers and with stiffer clustered protocadherin ectodomains facilitating overlap that favors binding specificity over mechanical resilience. Overall, our simulations provide insights into the molecular mechanics of single cadherin dimers relevant in the formation of cellular junctions essential for tissue function.

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Orientation Dependent Mechanical Responses and Plastic Deformation Mechanisms of ZnSe Nano Films under Nanoindentation

Nanomaterials ◽

10.3390/nano11113014 ◽

2021 ◽

Vol 11 (11) ◽

pp. 3014

Author(s):

Chao Xu ◽

Futi Liu ◽

Chunmei Liu ◽

Pei Wang ◽

Huaping Liu

Keyword(s):

Plastic Deformation ◽

Elastic Recovery ◽

Structural Evolution ◽

Atomic Displacement ◽

Deformation Mechanisms ◽

Formation Mechanisms ◽

Plastic Deformations ◽

Mechanical Responses ◽

Displacement Vectors ◽

Dynamics Simulations

Although ZnSe has been widely studied due to its attractive electronic and optoelectronic properties, limited data on its plastic deformations are available. Through molecular dynamics simulations, we have investigated the indentations on the (001), (110), and (111) planes of ZnSe nano films. Our results indicate that the elastic modulus, incipient plasticity, elastic recovery ratio, and the structural evolutions during the indenting process of ZnSe nano films show obvious anisotropy. To analyze the correlation of structural evolution and mechanical responses, the atomic displacement vectors, atomic arrangements, and the dislocations of the indented samples are analyzed. Our simulations revealed that the plastic deformations of the indented ZnSe nano films are dominated by the nucleation and propagation of 1/2<110> type dislocations, and the symmetrically distributed prismatic loops emitted during the indenting process are closely related with the mechanical properties. By studying the evolutions of microstructures, the formation process of the dislocations, as well as the formation mechanisms of the emitted prismatic loops under the indented crystalline planes are discussed. The results presented in this work not only provide an answer for the questions about indentation responses of ZnSe nano films, but also offer insight into its plastic deformation mechanisms.

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Kinetic and structural mechanism for DNA unwinding by a non-hexameric helicase

Nature Communications ◽

10.1038/s41467-021-27304-6 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Sean P. Carney ◽

Wen Ma ◽

Kevin D. Whitley ◽

Haifeng Jia ◽

Timothy M. Lohman ◽

...

Keyword(s):

Optical Tweezers ◽

Single Molecule ◽

Atp Hydrolysis ◽

Variable Number ◽

Structural Basis ◽

Variable Step Size ◽

Dna Unwinding ◽

Step Size ◽

Structural Mechanism ◽

Dynamics Simulations

AbstractUvrD, a model for non-hexameric Superfamily 1 helicases, utilizes ATP hydrolysis to translocate stepwise along single-stranded DNA and unwind the duplex. Previous estimates of its step size have been indirect, and a consensus on its stepping mechanism is lacking. To dissect the mechanism underlying DNA unwinding, we use optical tweezers to measure directly the stepping behavior of UvrD as it processes a DNA hairpin and show that UvrD exhibits a variable step size averaging ~3 base pairs. Analyzing stepping kinetics across ATP reveals the type and number of catalytic events that occur with different step sizes. These single-molecule data reveal a mechanism in which UvrD moves one base pair at a time but sequesters the nascent single strands, releasing them non-uniformly after a variable number of catalytic cycles. Molecular dynamics simulations point to a structural basis for this behavior, identifying the protein-DNA interactions responsible for strand sequestration. Based on structural and sequence alignment data, we propose that this stepping mechanism may be conserved among other non-hexameric helicases.

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The SARS-CoV-2 Exerts a Distinctive Strategy for Interacting with the ACE2 Human Receptor

Viruses ◽

10.3390/v12050497 ◽

2020 ◽

Vol 12 (5) ◽

pp. 497 ◽

Cited By ~ 39

Author(s):

Esther S. Brielle ◽

Dina Schneidman-Duhovny ◽

Michal Linial

Keyword(s):

Cell Receptor ◽

Host Recognition ◽

Interface Residue ◽

Binding Affinities ◽

Binding Interface ◽

Residue Contacts ◽

High Infection ◽

Dynamics Simulations ◽

Insight Into ◽

Human Receptor

The COVID-19 disease has plagued over 200 countries with over three million cases and has resulted in over 200,000 deaths within 3 months. To gain insight into the high infection rate of the SARS-CoV-2 virus, we compare the interaction between the human ACE2 receptor and the SARS-CoV-2 spike protein with that of other pathogenic coronaviruses using molecular dynamics simulations. SARS-CoV, SARS-CoV-2, and HCoV-NL63 recognize ACE2 as the natural receptor but present a distinct binding interface to ACE2 and a different network of residue–residue contacts. SARS-CoV and SARS-CoV-2 have comparable binding affinities achieved by balancing energetics and dynamics. The SARS-CoV-2–ACE2 complex contains a higher number of contacts, a larger interface area, and decreased interface residue fluctuations relative to the SARS-CoV–ACE2 complex. These findings expose an exceptional evolutionary exploration exerted by coronaviruses toward host recognition. We postulate that the versatility of cell receptor binding strategies has immediate implications for therapeutic strategies.

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Adaptive Load-Balancing for Force-Decomposition Based 3-Body Molecular Dynamics Simulations in A Heterogeneous Distributed Environment with Variable Number of Processors

2007 International Conference on Parallel Processing (ICPP 2007) ◽

10.1109/icpp.2007.11 ◽

2007 ◽

Cited By ~ 1

Author(s):

J.V. Sumanth ◽

David R. Swanson ◽

Hong Jiang

Keyword(s):

Molecular Dynamics ◽

Load Balancing ◽

Molecular Dynamics Simulations ◽

Variable Number ◽

Distributed Environment ◽

Dynamics Simulations ◽

Force Decomposition

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Glycosyl phosphatidylinositol--anchored T-cadherin mediates calcium-dependent, homophilic cell adhesion.

The Journal of Cell Biology ◽

10.1083/jcb.119.2.451 ◽

1992 ◽

Vol 119 (2) ◽

pp. 451-461 ◽

Cited By ~ 111

Author(s):

D J Vestal ◽

B Ranscht

Keyword(s):

Cell Adhesion ◽

Homophilic Binding ◽

Transfected Cells ◽

Glycosyl Phosphatidylinositol ◽

Calcium Dependent ◽

Monolayer Cultures ◽

Classical Cadherins ◽

Intracellular Proteins ◽

Cellular Aggregation ◽

Homophilic Adhesion

Cadherins are a family of cell adhesion molecules that exhibit calcium-dependent, homophilic binding. Their function depends on both an HisAlaVal sequence in the first extracellular domain, EC1, and the interaction of a conserved cytoplasmic region with intracellular proteins. T-cadherin is an unusual member of the cadherin family that lacks the HisAlaVal motif and is anchored to the membrane through a glycosyl phosphatidylinositol moiety (Ranscht, B., and M. T. Dours-Zimmermann. 1991. Neuron. 7:391-402). To assay the function of T-cadherin in cell adhesion, we have transfected T-cadherin cDNA into CHO cells. Two proteins, mature T-cadherin and the uncleaved T-cadherin precursor, were produced from T-cadherin cDNA. The T-cadherin proteins differed from classical cadherins in several aspects. First, the uncleaved T-cadherin precursor was expressed, together with mature T-cadherin, on the surface of the transfected cells. Second, in the absence of calcium, T-cadherin was more resistant to proteolytic cleavage than other cadherins. Lastly, in contrast to classical cadherins, T-cadherin was not concentrated into cell-cell contacts between transfected cells in monolayer cultures. In cellular aggregation assays, T-cadherin induced calcium-dependent, homophilic adhesion which was abolished by treatment of T-cadherin-transfected cells with phosphatidylinositol-specific phospholipase C. These results demonstrate that T-cadherin is a functional cadherin that differs in several properties from classical cadherins. The function of T-cadherin in homophilic cell recognition implies that the mechanism of T-cadherin-induced adhesion is distinct from that of classical cadherins.

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The SARS-CoV-2 exerts a distinctive strategy for interacting with the ACE2 human receptor

10.1101/2020.03.10.986398 ◽

2020 ◽

Cited By ~ 11

Author(s):

Esther S. Brielle ◽

Dina Schneidman-Duhovny ◽

Michal Linial

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulations ◽

Cell Receptor ◽

Host Recognition ◽

Interface Residue ◽

Binding Affinities ◽

Temporal Dimension ◽

Binding Interface ◽

Residue Contacts ◽

Dynamics Simulations

AbstractThe COVID-19 disease has plagued over 110 countries and has resulted in over 4,000 deaths within 10 weeks. We compare the interaction between the human ACE2 receptor and the SARS-CoV-2 spike protein with that of other pathogenic coronaviruses using molecular dynamics simulations. SARS-CoV, SARS-CoV-2, and HCoV-NL63 recognize ACE2 as the natural receptor but present a distinct binding interface to ACE2 and a different network of residue-residue contacts. SARS-CoV and SARS-CoV-2 have comparable binding affinities achieved by balancing energetics and dynamics. The SARS-CoV-2–ACE2 complex contains a higher number of contacts, a larger interface area, and decreased interface residue fluctuations relative to SARS-CoV. These findings expose an exceptional evolutionary exploration exerted by coronaviruses toward host recognition. We postulate that the versatility of cell receptor binding strategies has immediate implications on therapeutic strategies.One Sentence SummaryMolecular dynamics simulations reveal a temporal dimension of coronaviruses interactions with the host receptor.

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Development and Testing of an All-Atom Force Field for Diketopyrrolopyrrole Polymers with Conjugated Substituents

10.26434/chemrxiv.12705695.v2 ◽

2020 ◽

Author(s):

Vivek Sundaram ◽

Alexey V. Lyulin ◽

Björn Baumeier

Keyword(s):

Force Field ◽

Density Functional ◽

Density Functional Theory Calculations ◽

Building Blocks ◽

Variable Number ◽

Polymer Chains ◽

Relaxation Processes ◽

Polymer Backbone ◽

Dynamics Simulations ◽

The Individual

We develop an all-atom force field for a series of diketopyrrolopyrrole polymers with two aromatic pyridine substituents and variable number of pi-conjugated thiophene units in the backbone, used as donor material in organic photovoltaic devices. Available intra-fragment parameterizations of the individual fragment building blocks are combined with inter-fragment bonded and non-bonded parameters explicitly derived from density-functional theory calculations. To validate the force field we perform classical molecular dynamics simulations of single polymer chains with 1, 2, and 3 thiophenes in good and bad solvents, and of melts. We observe the expected dependence of the chain conformation on the solvent quality, with the chain collapsing in water, and swelling in chloroform. The glass transition temperature for the polymer melts is found to be in the range of 340K to 370K. Analysis of the mobility of the conjugated segments in the polymer backbone reveals two relaxation processes: a fast one with a characteristic time at room temperature on the order of 10ps associated with nearly harmonic vibrations and a slow one on the order of 100 associated with temperature activated cis-trans transitions.

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Decomposition of the SARS-CoV-2-ACE2 interface reveals a common trend among emerging viral variants

10.1101/2021.05.28.446149 ◽

2021 ◽

Author(s):

Eileen Socher ◽

Marcus Conrad ◽

Lukas Heger ◽

Friedrich Paulsen ◽

Heinrich Sticht ◽

...

Keyword(s):

Amino Acid ◽

Host Cell ◽

Cell Receptor ◽

Cell Interaction ◽

Therapeutic Interventions ◽

Host Cell Receptor ◽

Common Trend ◽

Binding Interface ◽

Dynamics Simulations ◽

Viral Surface

New viral variants of the SARS-CoV-2 virus show enhanced infectivity compared to wild type, resulting in an altered pandemic situation in affected areas. These variants are the B.1.1.7 (United Kingdom), B.1.1.7 with the additional E484K mutation, the B.1.351 variant (South Africa) and the P.1 variant (Brazil). Understanding the binding modalities between these viral variants and the host cell receptor ACE2 allows depicting changes, but also common motifs of virus-host cell interaction. The trimeric spike protein expressed at the viral surface contains the receptor-binding domain (RBD) that forms the molecular interface with ACE2. All the above-mentioned variants carry between one and three amino acid exchanges within the interface-forming region of the RBD, thereby altering the binding interface with ACE2. Using molecular dynamics simulations and decomposition of the interaction energies between the RBD and ACE2, we identified phenylalanine 486, glutamine 498, threonine 500 and tyrosine 505 as important interface-forming residues across viral variants. We also suggest a reduced binding energy between RBD and ACE2 in viral variants with higher infectivity, attributed to residue-specific differences in electrostatic interaction energy. Importantly, individual amino acid exchanges not only influence the affected position, but also alter the conformation of surrounding residues and affect their interaction potential as well. We demonstrate how computational methods can help to identify changed as well as common motifs across viral variants. These identified motifs might play a crucial role, in the strategical development of therapeutic interventions against the fast mutating SARS-CoV-2 virus.

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Simulation of Mechanical Elongation and Compression of Nanostructures

MRS Proceedings ◽

10.1557/opl.2016.42 ◽

2016 ◽

Vol 1817 ◽

Cited By ~ 1

Author(s):

Sergio Mejía-Rosales ◽

Carlos Fernández-Navarro

Keyword(s):

Strain Analysis ◽

Elastic Response ◽

Gold Nanowires ◽

Lateral Compression ◽

Direction Parallel ◽

Jones Potential ◽

Lennard Jones ◽

Deformation Regime ◽

Dynamics Simulations ◽

Fcc Structure

ABSTRACTWe present a set of Molecular Dynamics simulations of the axial elongation of gold nanowires, and the compression of silver decahedral nanowires by a carbon AFM tip. We used Sutton and Chen multibody potentials to describe the metallic interactions, a Tersoff potential to simulate the carbon-carbon interactions, and a 6-12 Lennard-Jones potential to describe the metal-carbon interactions. In the elongation simulations, gold nanowires were subjected to strain at several rates, and we concentrated our attention in the specific case of a wire with an atomistic arrangement based on the intercalation of icosahedral motifs forming a Boerdijk-Coxeter (BCB) spiral, and compare it against results of nanowires with fcc structure and (001), (011), and (111) orientations. We found that the BCB nanowire is more resistant to breakage than the fcc nanowires. In the simulations of lateral compression, we made a strain analysis of the trajectories, finding that when a gold decahedral nanowire is compressed by the AFM tip in a direction parallel to a (100) face, the plastic deformation regime is considerably larger than in the case of compression exerted in a direction parallel to a twin plane, where the fracture of the wire comes almost immediately after the elastic range ends. The strain distribution and elastic response in the compression of nanoparticles with different geometries is also discussed.

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