TY - JOUR
T1 - Hot spots and their contribution to the self-assembly of the viral capsid
T2 - In silico prediction and analysis
AU - Díaz-Valle, Armando
AU - Falcón-González, José Marcos
AU - Carrillo-Tripp, Mauricio
N1 - Publisher Copyright:
© 2019 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2019/12
Y1 - 2019/12
N2 - The viral capsid is a macromolecular complex formed by a defined number of self-assembled proteins, which, in many cases, are biopolymers with an identical amino acid sequence. Specific protein–protein interactions (PPI) drive the capsid self-assembly process, leading to several distinct protein interfaces. Following the PPI hot spot hypothesis, we present a conservation-based methodology to identify those interface residues hypothesized to be crucial elements on the self-assembly and thermodynamic stability of the capsid. We validate the predictions through a rigorous physical framework which integrates molecular dynamics simulations and free energy calculations by Umbrella sampling and the potential of mean force using an all-atom molecular representation of the capsid proteins of an icosahedral virus in an explicit solvent. Our results show that a single mutation in any of the structure-conserved hot spots significantly perturbs the quaternary protein–protein interaction, decreasing the absolute value of the binding free energy, without altering the protein’s secondary nor tertiary structure. Our conservation-based hot spot prediction methodology can lead to strategies to rationally modulate the capsid’s thermodynamic properties.
AB - The viral capsid is a macromolecular complex formed by a defined number of self-assembled proteins, which, in many cases, are biopolymers with an identical amino acid sequence. Specific protein–protein interactions (PPI) drive the capsid self-assembly process, leading to several distinct protein interfaces. Following the PPI hot spot hypothesis, we present a conservation-based methodology to identify those interface residues hypothesized to be crucial elements on the self-assembly and thermodynamic stability of the capsid. We validate the predictions through a rigorous physical framework which integrates molecular dynamics simulations and free energy calculations by Umbrella sampling and the potential of mean force using an all-atom molecular representation of the capsid proteins of an icosahedral virus in an explicit solvent. Our results show that a single mutation in any of the structure-conserved hot spots significantly perturbs the quaternary protein–protein interaction, decreasing the absolute value of the binding free energy, without altering the protein’s secondary nor tertiary structure. Our conservation-based hot spot prediction methodology can lead to strategies to rationally modulate the capsid’s thermodynamic properties.
KW - Alanine-scanning
KW - Binding free energy
KW - Free energy
KW - Functional dimer
KW - Molecular dynamics
KW - Protein-Protein interaction
KW - Site-directed mutagenesis
KW - Structural conservation
UR - http://www.scopus.com/inward/record.url?scp=85075667089&partnerID=8YFLogxK
U2 - 10.3390/ijms20235966
DO - 10.3390/ijms20235966
M3 - Artículo
C2 - 31783519
AN - SCOPUS:85075667089
SN - 1661-6596
VL - 20
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 23
M1 - 5966
ER -