scholarly journals The Landscape-Based Protein Stability Analysis and Network Modeling of Multiple Conformational States of the SARS-CoV-2 Spike D614 Mutant: Conformational Plasticity and Frustration-Driven Allostery as Energetic Drivers of Highly Transmissible Spike Variant

2021 ◽  
Author(s):  
Gennady Verkhivker ◽  
Steve Agajanian ◽  
Ryan Kassab ◽  
Keerthi Krishnan
Keyword(s):  
Protein Stability ◽  
Mechanistic Model ◽  
Spike Protein ◽  
Coarse Grained ◽  
Virus Infectivity ◽  
Conformational States ◽  
Conformational Substates ◽  
Functional Studies ◽  
Functional Regions ◽  
Coarse Grained Simulations

The structural and functional studies of the SARS-CoV-2 spike protein variants revealed an important role of the D614G mutation that is shared across many variants of concern(VOCs), suggesting the effect of this mutation on the enhanced virus infectivity and transmissibility. The recent structural and biophysical studies provided important evidence about multiple conformational substates of the D614G spike protein. The development of a plausible mechanistic model which can explain the experimental observations from a more unified thermodynamic perspective is an important objective of the current work. In this study, we employed efficient and accurate coarse-grained simulations of multiple structural substates of the D614G spike trimers together with the ensemble-based mutational frustration analysis to characterize the dynamics signatures of the conformational landscapes. By combining the local frustration profiling of the conformational states with residue-based mutational scanning of protein stability and network analysis of allosteric interactions and communications, we determine the patterns of mutational sensitivity in the functional regions and sites of variants. We found that the D614G mutation may induce a considerable conformational adaptability of the open states in the SARS-CoV-2 spike protein without compromising folding stability and integrity of the spike protein. The results suggest that the D614G mutant may employ a hinge-shift mechanism in which the dynamic couplings between the site of mutation and the inter-protomer hinge modulate the inter-domain interactions, global mobility change and the increased stability of the open form. This study proposes that mutation-induced modulation of the conformational flexibility and energetic frustration at the inter-protomer interfaces may serve as an efficient mechanism for allosteric regulation of the SARS-CoV-2 spike proteins.

scholarly journals Conformational Flexibility and Local Frustration in the Functional States of the SARS-CoV-2 Spike B.1.1.7 and B.1.351 Variants: Mutation-Induced Allosteric Modulation Mechanism of Functional Dynamics and Protein Stability

2021 ◽  
Author(s):  
Gennady Verkhivker
Keyword(s):  
Protein Stability ◽  
Cell Receptor ◽  
Spike Protein ◽  
Coarse Grained ◽  
Virus Infectivity ◽  
Functional Changes ◽  
Conformational Substates ◽  
Functional Relationships ◽  
Functional Dynamics ◽  
Open States

The experimental and computational studies of the SARS-CoV-2 spike protein variants revealed an important role of the D614G mutation that is shared across variants of concern(VOCs), linking the effect of this mutation with the enhanced virus infectivity and transmissibility. The recent structural and biophysical studies characterized the closed and open states of the B.1.1.7 (B.1.1.7) and B.1.351 (Beta) spike variants allowing for a more detailed atomistic characterization of the conformational landscapes and functional changes. In this study, we employed coarse-grained simulations of the SARS-CoV-2 spike variant trimers together with the ensemble-based mutational frustration analysis to characterize the dynamics signatures of the conformational landscapes. By combining the local frustration analysis of the conformational ensembles with collective dynamics and residue-based mutational scanning of protein stability, we determine protein stability hotspots and identify potential energetic drivers favoring the receptor-accessible open spike states for the B.1.1.7 and B.1.351 spike variants. Through mutational scanning of protein stability changes we quantify mutational adaptability of the S-G614, S-B.1.1.7 and S-B.1.351 variants in different functional forms. Using this analysis, we found a significant conformational and mutational plasticity of the open states for all studied variants. The results of this study suggest that modulation of the energetic frustration at the inter-protomer interfaces can serve as a mechanism for allosteric couplings between mutational sites, the inter-protomer hinges of functional motions and motions of the receptor-binding domain required for binding of the host cell receptor. The proposed mechanism of mutation-induced energetic frustration may result in the greater adaptability and the emergence of multiple conformational substates in the open form. This study also suggested functional relationships between mutation-induced modulation of protein dynamics, local frustration and allosteric regulation of the SARS-CoV-2 spike protein.

Grand-Reaction Method for Simulations of Ionization Equilibria and Ion Partitioning in a Broad Range of pH and Ionic Strength

2019 ◽  
Author(s):  
Jonas Landsgesell ◽  
Oleg Rud ◽  
Pascal Hebbeker ◽  
Raju Lunkad ◽  
Peter Košovan ◽  
...  
Keyword(s):  
Mean Field ◽  
Coarse Grained ◽  
Reactive System ◽  
Acid Base ◽  
Buffer Solution ◽  
Reaction Method ◽  
Ionization Equilibria ◽  
Coarse Grained Simulations ◽  
Ph Range ◽  
Weak Polyelectrolytes

We introduce the grand-reaction method for coarse-grained simulations of acid-base equilibria in a system coupled to a reservoir at a given pH and concentration of added salt. It can be viewed as an extension of the constant-pH method and the reaction ensemble, combining explicit simulations of reactions within the system, and grand-canonical exchange of particles with the reservoir. Unlike the previously introduced methods, the grand-reaction method is applicable to acid-base equilibria in the whole pH range because it avoids known artifacts. However, the method is more general, and can be used for simulations of any reactive system coupled to a reservoir of a known composition. To demonstrate the advantages of the grand-reaction method, we simulated a model system: A solution of weak polyelectrolytes in equilibrium with a buffer solution. By carefully accounting for the exchange of all constituents, the method ensures that all chemical potentials are equal in the system and in the multi-component reservoir. Thus, the grand-reaction method is able to predict non-monotonic swelling of weak polyelectrolytes as a function of pH, that has been known from mean-field predictions and from experiments but has never been observed in coarse-grained simulations. Finally, we outline possible extensions and further generalizations of the method, and provide a set of guidelines to enable safe usage of the method by a broad community of users.<br><br>

scholarly journals Submarine lava deltas of the 2018 eruption of Kīlauea volcano

2021 ◽  
Vol 83 (4) ◽  
Author(s):  
S. Adam Soule ◽  
Michael Zoeller ◽  
Carolyn Parcheta
Keyword(s):  
Grain Size ◽  
Pore Pressure ◽  
Mechanistic Model ◽  
Large Fraction ◽  
Volcanic Hazards ◽  
Lava Flows ◽  
Coarse Grained ◽  
Fine Grained ◽  
Fine Grain ◽  
Delta Formation

AbstractHawaiian and other ocean island lava flows that reach the coastline can deposit significant volumes of lava in submarine deltas. The catastrophic collapse of these deltas represents one of the most significant, but least predictable, volcanic hazards at ocean islands. The volume of lava deposited below sea level in delta-forming eruptions and the mechanisms of delta construction and destruction are rarely documented. Here, we report on bathymetric surveys and ROV observations following the Kīlauea 2018 eruption that, along with a comparison to the deltas formed at Pu‘u ‘Ō‘ō over the past decade, provide new insight into delta formation. Bathymetric differencing reveals that the 2018 deltas contain more than half of the total volume of lava erupted. In addition, we find that the 2018 deltas are comprised largely of coarse-grained volcanic breccias and intact lava flows, which contrast with those at Pu‘u ‘Ō‘ō that contain a large fraction of fine-grained hyaloclastite. We attribute this difference to less efficient fragmentation of the 2018 ‘a‘ā flows leading to fragmentation by collapse rather than hydrovolcanic explosion. We suggest a mechanistic model where the characteristic grain size influences the form and stability of the delta with fine grain size deltas (Pu‘u ‘Ō‘ō) experiencing larger landslides with greater run-out supported by increased pore pressure and with coarse grain size deltas (Kīlauea 2018) experiencing smaller landslides that quickly stop as the pore pressure rapidly dissipates. This difference, if validated for other lava deltas, would provide a means to assess potential delta stability in future eruptions.

Insights Into Crowding Effects on Protein Stability From a Coarse-Grained Model

2009 ◽  
Vol 131 (7) ◽  
Author(s):  
Vincent K. Shen ◽  
Jason K. Cheung ◽  
Jeffrey R. Errington ◽  
Thomas M. Truskett
Keyword(s):  
Protein Stability ◽  
Coarse Grained ◽  
Protein Solutions ◽  
Native State ◽  
High Concentration ◽  
Coarse Grained Model ◽  
Excluded Volume Effects ◽  
Thermodynamic Phase ◽  
Broad Interest ◽  
Liquid Liquid Phase Separation

Proteins aggregate and precipitate from high concentration solutions in a wide variety of problems of natural and technological interest. Consequently, there is a broad interest in developing new ways to model the thermodynamic and kinetic aspects of protein stability in these crowded cellular or solution environments. We use a coarse-grained modeling approach to study the effects of different crowding agents on the conformational equilibria of proteins and the thermodynamic phase behavior of their solutions. At low to moderate protein concentrations, we find that crowding species can either stabilize or destabilize the native state, depending on the strength of their attractive interaction with the proteins. At high protein concentrations, crowders tend to stabilize the native state due to excluded volume effects, irrespective of the strength of the crowder-protein attraction. Crowding agents reduce the tendency of protein solutions to undergo a liquid-liquid phase separation driven by strong protein-protein attractions. The aforementioned equilibrium trends represent, to our knowledge, the first simulation predictions for how the properties of crowding species impact the global thermodynamic stability of proteins and their solutions.

scholarly journals THER-09. ONCOLYTIC ADENOVIRUS, DNX-2401, FOR NAIVE DIFFUSE INTRINSIC PONTINE GLIOMAS: A PHASE I CLINICAL TRIAL

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii473-iii473
Author(s):  
Ignacio Iñigo-Marco ◽  
Marisol Gonzalez-Huarriz ◽  
Marc García-Moure ◽  
Ibon Tamayo ◽  
Sandra Hervas ◽  
...  
Keyword(s):  
T Cell ◽  
Neutralizing Antibodies ◽  
Immune Cell ◽  
Combined Treatment ◽  
Intratumoral Injection ◽  
Post Treatment ◽  
Virus Infectivity ◽  
Tumor Biopsy ◽  
Functional Studies ◽  
Cell Diversity

Abstract The objective of this trial is to determine the safety, tolerability, and toxicity of DNX-2401 in newly diagnosed DIPG patients (NCT03178032) followed by radiotherapy. Secondary endpoints are overall survival at 12 months, percentage of responses and induced immune response against tumor. Tumor biopsy was performed through the cerebellar peduncle, followed by intratumoral injection of DNX-2401 (N=12). Three patients were treated with 1x1010vp and given the lack of toxicity we escalated to 5x1010vp. The procedure was well tolerated and reduced tumor volume was demonstrated in all patients after combined treatment (virus + radiotherapy). We performed molecular studies (RNAseq and the Oncomine Childhood Research Panel from Thermo Fisher). The immune cell composition of the biopsies pre-virus injection was assessed using multiplexed quantitative immunofluorescence. T cells were hardly detectable in these tumors while macrophages were abundant. Using a multiplexed TCR-sequencing mRNA-based assay to analyze 18 available paired pre- and post-treatment samples from the trial, we detected increased clonal T cell diversity following treatment with the virus. We also measured pre and post treatment neutralizing antibodies and their relationship with survival. Finally, we performed functional studies using 2 cell lines isolated from patients included in this trial to assess the response to the virus (infectivity, viability, T-cell recognition). In summary, the virus has shown safety and efficacy in some patients. The information obtained in this clinical study would aid understanding the response of DIPG patients to viral therapies and, therefore, to better tailor this strategy to improve the survival of these patients.

scholarly journals Prediction and validation of protein intermediate states from structurally rich ensembles and coarse-grained simulations

2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Laura Orellana ◽  
Ozge Yoluk ◽  
Oliver Carrillo ◽  
Modesto Orozco ◽  
Erik Lindahl
Keyword(s):  
Coarse Grained ◽  
Intermediate States ◽  
Coarse Grained Simulations

Effect of oligonucleic acid (ONA) backbone features on assembly of ONA–star polymer conjugates: a coarse-grained molecular simulation study

Soft Matter ◽  
2017 ◽  
Vol 13 (38) ◽  
pp. 6770-6783 ◽  
Author(s):  
Joshua E. Condon ◽  
Arthi Jayaraman
Keyword(s):  
Molecular Simulation ◽  
Simulation Study ◽  
Coarse Grained ◽  
Star Polymer ◽  
Backbone Flexibility ◽  
Polymer Architecture ◽  
Polymer Conjugates ◽  
Coarse Grained Simulations

Using coarse-grained simulations, we study the effect of varying oligonucleic acid (ONA) backbone flexibility, ONA charge and star polymer architecture on structure and thermodynamics of ONA–star polymer conjugates assembly.

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