scholarly journals D614G substitution enhances the stability of trimeric SARS-CoV-2 spike protein

2020 ◽  
Author(s):  
Arangasamy Yazhini ◽  
Das Swayam Prakash Sidhanta ◽  
Narayanaswamy Srinivasan
Keyword(s):  
Thermodynamic Stability ◽  
Energy Difference ◽  
Spike Protein ◽  
Interaction Energies ◽  
Free Energy Difference ◽  
Residue Interaction ◽  
Ancestral Virus ◽  
Glycine Substitution ◽  
Favourable Environment ◽  
The Stability

AbstractSARS-CoV-2 spike protein with D614G substitution has become the dominant variant in the ongoing COVID-19 pandemic. Several studies to characterize the new virus expressing G614 variant show that it exhibits increased infectivity compared to the ancestral virus having D614 spike protein. Here, using in-silico mutagenesis and energy calculations, we analyzed inter-residue interaction energies and thermodynamic stability of the dominant (G614) and the ancestral (D614) variants of spike protein trimer in ‘closed’ and ‘partially open’ conformations. We find that the local interactions mediated by aspartate at the 614th position are energetically frustrated and create unfavourable environment. Whereas, glycine at the same position confers energetically favourable environment and strengthens intra-as well as inter-protomer association. Such changes in the local interaction energies enhance the thermodynamic stability of the spike protein trimer as free energy difference (ΔΔG) upon glycine substitution is −2.6 kcal/mol for closed conformation and −2.0 kcal/mol for open conformation. Our results on the structural and energetic basis of enhanced stability hint that G614 may confer increased availability of functional form of spike protein trimer and consequent in higher infectivity than the D614 variant.

scholarly journals D614G substitution at the hinge region enhances the stability of trimeric SARS-CoV-2 spike protein

2021 ◽  
Author(s):  
Arangasamy Yazhini ◽  
Das Swayam Prakash Sidhanta ◽  
Narayanaswamy Sriniva
Keyword(s):  
Free Energy ◽  
Thermodynamic Stability ◽  
Normal Mode Analysis ◽  
Protein Flexibility ◽  
Energy Difference ◽  
Hinge Region ◽  
Spike Protein ◽  
Mode Analysis ◽  
Free Energy Difference ◽  
Residue Interaction

Abstract Background Spike protein is a key player in the SARS-CoV-2 infection by mediating primary contact between the virus and host cell surface. In the current COVID-19 pandemic, a variant of SARS-CoV-2 having D614G substitution in the spike protein has become dominant world-wide. Initial characterization of the virus shows that the G614 variant is more infectious and has higher fitness than the ancestral (D614) variant. In this study, we analyzed the significance of the D614G substitution on the protein flexibility, inter-residue interaction energies and thermostability of the spike protein trimer. Results Using Gaussian network model-based normal mode analysis, we demonstrate that D614G substitution occurs at hinge region that facilitates domain-domain motions between receptor binding domain and S2 region of the spike protein. Further, in-silico mutagenesis and inter-residue energy calculations reveal that contacts involving D614 are energetically frustrated whereas contacts involving G614 are energetically favourable implying the substitution strengthens intra- as well as inter-protomers association. Upon glycine substitution, free energy difference (ΔΔG) is -2.6 kcal/mol for closed and − 2.0 kcal/mol for 1-RBD up conformation i.e., thermodynamic stability has increased. When we perform reverse mutation in the structures of spike protein having G614 substitution, we observe that the free energy difference is 6.6 kcal/mol and 6.3 kcal/mol for closed and 1-RBD up conformations respectively indicating lowered thermodynamic stability. Together, these observations suggest that D614G substitution could modulate the flexibility of spike protein and confer enhanced thermodynamic stability. Conclusion Our results on protein flexibility and energetic basis of enhanced stability hint that G614 likely increases the availability of functional form of spike trimer thereby associated to increased infectivity.

scholarly journals D614G substitution at the hinge region enhances the stability of trimeric SARS-CoV-2 spike protein

2021 ◽  
Vol 17 (3) ◽  
pp. 439-445
Author(s):  
Arangasamy Yazhini ◽  
◽  
◽  
Keyword(s):  
Free Energy ◽  
Thermodynamic Stability ◽  
Normal Mode Analysis ◽  
Protein Structures ◽  
Energy Difference ◽  
Hinge Region ◽  
Spike Protein ◽  
Mode Analysis ◽  
The Stability ◽  
Domain Motions

Mutations in the spike protein of SARS-CoV-2 are the major causes for the modulation of ongoing COVID-19 infection. Currently, the D614G substitution in the spike protein has become dominant worldwide. It is associated with higher infectivity than the ancestral (D614) variant. We demonstrate using Gaussian network model-based normal mode analysis that the D614G substitution occurs at the hinge region that facilitates domain-domain motions between receptor binding domain and S2 region of the spike protein. Computer-aided mutagenesis and inter-residue energy calculations reveal that contacts involving D614 are energetically frustrated. However, contacts involving G614 are energetically favourable, implying the substitution strengthens residue contacts that are formed within as well as between protomers. We also find that the free energy difference (ΔΔG) between two variants is -2.6 kcal/mol for closed and -2.0 kcal/mol for 1-RBD up conformation. Thus, the hermodynamic stability has increased upon D614G substitution. Whereas the reverse mutation in spike protein structures having G614 substitution has resulted in the free energy differences of 6.6 kcal/mol and 6.3 kcal/mol for closed and 1-RBD up conformations, respectively, indicating that the overall thermodynamic stability has decreased. These results suggest that the D614G substitution modulates the flexibility of spike protein and confers enhanced thermodynamic stability irrespective of conformational states. This data concurs with the known information demonstrating increased availability of the functional form of spike protein trimer upon D614G substitution.

scholarly journals Atomic insights into the effects of pathological mutants through the disruption of hydrophobic core in the prion protein

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Juhwan Lee ◽  
Iksoo Chang ◽  
Wookyung Yu
Keyword(s):  
Amino Acids ◽  
Protein Folding ◽  
Prion Protein ◽  
Hydrophobic Interactions ◽  
Energy Difference ◽  
Hydrophobic Core ◽  
Free Energy Difference ◽  
The Stability ◽  
Simulation Time ◽  
Folding Free Energy

AbstractDestabilization of prion protein induces a conformational change from normal prion protein (PrPC) to abnormal prion protein (PrPSC). Hydrophobic interaction is the main driving force for protein folding, and critically affects the stability and solvability. To examine the importance of the hydrophobic core in the PrP, we chose six amino acids (V176, V180, T183, V210, I215, and Y218) that make up the hydrophobic core at the middle of the H2-H3 bundle. A few pathological mutants of these amino acids have been reported, such as V176G, V180I, T183A, V210I, I215V, and Y218N. We focused on how these pathologic mutations affect the hydrophobic core and thermostability of PrP. For this, we ran a temperature-based replica-exchange molecular dynamics (T-REMD) simulation, with a cumulative simulation time of 28 μs, for extensive ensemble sampling. From the T-REMD ensemble, we calculated the protein folding free energy difference between wild-type and mutant PrP using the thermodynamic integration (TI) method. Our results showed that pathological mutants V176G, T183A, I215V, and Y218N decrease the PrP stability. At the atomic level, we examined the change in pair-wise hydrophobic interactions from valine-valine to valine-isoleucine (and vice versa), which is induced by mutation V180I, V210I (I215V) at the 180th–210th (176th–215th) pair. Finally, we investigated the importance of the π-stacking between Y218 and F175.

Thermodynamic Stability of Hexagonal and Rhombohedral Bn at Cvd Conditions from Van der Waals Corrected First Principles Calculations

2019 ◽  
Author(s):  
Henrik Pedersen ◽  
Björn Alling ◽  
Hans Högberg ◽  
Annop Ektarawong
Keyword(s):  
Thin Films ◽  
Thermodynamic Stability ◽  
First Principles ◽  
Thermal Equilibrium ◽  
Density Functional ◽  
Van Der Waals ◽  
Chemical Vapor ◽  
First Principles Calculations ◽  
Functional Theory ◽  
The Stability

Thin films of boron nitride (BN), particularly the sp<sup>2</sup>-hybridized polytypes hexagonal BN (h-BN) and rhombohedral BN (r-BN) are interesting for several electronic applications given band gaps in the UV. They are typically deposited close to thermal equilibrium by chemical vapor deposition (CVD) at temperatures and pressures in the regions 1400-1800 K and 1000-10000 Pa, respectively. In this letter, we use van der Waals corrected density functional theory and thermodynamic stability calculations to determine the stability of r-BN and compare it to that of h-BN as well as to cubic BN and wurtzitic BN. We find that r-BN is the stable sp<sup>2</sup>-hybridized phase at CVD conditions, while h-BN is metastable. Thus, our calculations suggest that thin films of h-BN must be deposited far from thermal equilibrium.

Dynamic Transformation of Austenite at Temperatures above the Ae3

2018 ◽  
Vol 941 ◽  
pp. 633-638
Author(s):  
John Joseph Jonas ◽  
Clodualdo Aranas Jr. ◽  
Samuel F. Rodrigues
Keyword(s):  
Electron Microscopy ◽  
Driving Force ◽  
Energy Difference ◽  
Accelerated Cooling ◽  
Free Energy Difference ◽  
Dynamic Transformation ◽  
Plate Rolling ◽  
Temperature Transformation ◽  
Mn Steel ◽  
Kinetics Of

Under loading above the Ae3 temperature, austenite transforms displacively into Widmanstätten ferrite. Here the driving force for transformation is the net softening during the phase change while the obstacle consists of the free energy difference between austenite and ferrite as well as the work of shear accommodation and dilatation during the transformation. Once the driving force is higher than the obstacle, phase transformation occurs. This phenomenon was explored here by means of the optical and electron microscopy of a C-Mn steel deformed above their transformation temperatures. Strain-temperature-transformation (STT) curves are presented that accurately quantify the amount of dynamically formed ferrite; the kinetics of retransformation are also specified in the form of appropriate TTRT diagrams. This technique can be used to improve the models for transformation on accelerated cooling in strip and plate rolling.

Reduction of the oxidized bacteriochlorophyll dimer in reaction centers by ferrocene is dependent upon the driving force

2007 ◽  
Vol 11 (03) ◽  
pp. 205-211 ◽  
Author(s):  
László Kálmán ◽  
Arlene L. M. Haffa ◽  
JoAnn C. Williams ◽  
Neal W. Woodbury ◽  
James P. Allen
Keyword(s):  
Electron Transfer ◽  
Rate Constants ◽  
Ph Dependence ◽  
Photosynthetic Bacterium ◽  
Energy Difference ◽  
Reaction Centers ◽  
Free Energy Difference ◽  
Midpoint Potential ◽  
Bacteriochlorophyll Dimer ◽  
Purple Photosynthetic Bacterium

The rates of electron transfer from ferrocene to the oxidized bacteriochlorophyll dimer, P , in reaction centers from the purple photosynthetic bacterium Rhodobacter sphaeroides, were measured for a series of mutants in which the P / P + midpoint potentials range from 410 to 765 mV (Lin et al. Proc. Natl. Acad. Sci. USA 1994; 91: 10265-10269). The observed rate constant for each mutant was found to be linearly dependent upon the ferrocene concentration up to 50 μM. The electron transfer is described as a second order reaction with rate constants increasing from 1.5 to 35 × 106 M -1. s -1 with increasing P / P + midpoint potential. This dependence was tested for three additional mutants, each of which exhibits a pH dependence of the P / P + midpoint potential due to an electrostatic interaction with an introduced carboxylic group (Williams et al. Biochemistry 2001; 40: 15403-15407). For these mutants, the pH dependence of the bimolecular rate constants followed a sigmoidal pattern that could be described with a Henderson-Hasselbalch equation, attributable to the change of the free energy difference for the reaction due to deprotonation of the introduced carboxylic side chains.

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