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Molecular modeling and dynamic simulation of chicken Mx protein with the S631N polymorphism
Vijayakumar Gosu1, Donghyun Shin2,3, Ki-Duk Song1,2,3
1Department of Animal Biotechnology, Jeonbuk National University, Jeonju, Republic of Korea.
Abstract:
Myxovirus resistance (Mx) proteins are antiviral GTPases induced by type I interferons (IFNs). In chickens, a single Mx protein variant, S631N, has been suggested to possess antiviral activity. However, the impact of this variant on chicken Mx (chMx) protein structure and conformation has not been investigated. Hence, in this study, we applied computational methods such as molecular modeling, molecular dynamic simulation, inter domain motion and residue networks to examine the structure and dynamic behavior of wild-type and mutant chMx. At first, we built 3-dimensional structural models for both wild-type and mutant chMx proteins, which revealed that the structural organization of chMx was similar to that of human Mx proteins. Subsequently, molecular dynamics simulations revealed that angle variation around the hinge1 region led to the different stalk domain conformations between the wild-type and mutant chMx proteins. Domain motion analysis further suggested that the conformational differences in the loop region surrounded by the mutant residue may lead to an inclined stalk domain conformation in the mutant compared to the wild-type protein. In addition, we performed betweenness centrality analysis from residue interaction networks, to identify the crucial residues for intramolecular signal flow in chMx. The results of this study provided information on the differences in structure and dynamics between wild-type and mutant chMx, which may aid in understanding the structural features of the S631N mutant, that may be associated with chMx protein antiviral activity.Communicated by Ramaswamy H. Sarma.
Insights
Computational analysis reveals structural and dynamic differences between wild-type and S631N mutant chicken Mx (chMx) proteins. These findings may explain the antiviral activity of the chMx S631N variant.
Area of Science:
- Biochemistry
- Structural Biology
- Virology
Background:
- Myxovirus resistance (Mx) proteins are key antiviral GTPases induced by type I interferons (IFNs).
- A specific variant, S631N, in chicken Mx (chMx) protein is hypothesized to confer antiviral properties.
- The structural and conformational impact of the S631N mutation on chMx remains uncharacterized.
Purpose of the Study:
- To investigate the structural and dynamic behavior of wild-type and S631N mutant chMx proteins using computational methods.
- To elucidate how the S631N mutation affects chMx protein structure and conformation.
- To identify key residues involved in intramolecular signaling within chMx.
Main Methods:
- 3D structural modeling of wild-type and mutant chMx proteins.
- Molecular dynamics (MD) simulations to analyze protein dynamics.
- Inter-domain motion analysis.
- Residue network analysis (betweenness centrality) to identify crucial residues.
Main Results:
- 3D models showed chMx shares structural similarity with human Mx proteins.
- MD simulations indicated altered hinge1 region dynamics and distinct stalk domain conformations between wild-type and mutant chMx.
- Conformational changes in a loop region near the S631N mutation likely cause an inclined stalk domain in the mutant.
- Residue network analysis identified critical residues for intramolecular signal transmission.
Conclusions:
- This study provides novel insights into the structural and dynamic differences between wild-type and S631N mutant chMx proteins.
- The identified structural variations may underlie the enhanced antiviral activity associated with the chMx S631N variant.
- Understanding these molecular differences can inform future strategies for developing antiviral therapies.
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