The Role of Non‐covalent Interactions in the Molecular Recognition and Attachment of the Chikungunya Virus to the MXRA8 Receptor

The Chikungunya virus (CHIKV), transmitted by Aedes mosquitoes, initiates infection through direct engagement with MXRA8, a host receptor for arthritogenic alphaviruses. In this work, classical molecular dynamics simulations combined with qauantum descriptors of bonding interactions, including non-covalent interaction (NCI) plots, quantum theory of atoms in molecules (QTAIM), and natural bond orbital (NBO) calculations, are used to elucidate the nature and strength of the intermolecular interactions driving CHIKV recognition and attachment. We provide evidence to show that regardless of initial conditions, force fields, and software, the virus and receptor form a stable complex where the most prevalent interactions are due to arginine-aspartate contacts, but also come from the cooperative action of a large number of individually weak contacts, yielding an extended region of non-covalent direct protein <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:semantics><mml:mrow><mml:mtext>⋅⋅⋅</mml:mtext></mml:mrow> <mml:annotation>$\cdots$</mml:annotation></mml:semantics> </mml:math> protein, solvent-mediated protein <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:semantics><mml:mrow><mml:mtext>⋅⋅⋅</mml:mtext></mml:mrow> <mml:annotation>$\cdots$</mml:annotation></mml:semantics> </mml:math> protein, and glycan <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:semantics><mml:mrow><mml:mtext>⋅⋅⋅</mml:mtext></mml:mrow> <mml:annotation>$\cdots$</mml:annotation></mml:semantics> </mml:math> protein interactions. Based on quantum chemical calculations, we show that a good part of the stabilization of the CHIKV· · ·MXRA8 complex arises from the energetic contributions given by eight persistent direct protein <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:semantics><mml:mrow><mml:mtext>⋅⋅⋅</mml:mtext></mml:mrow> <mml:annotation>$\cdots$</mml:annotation></mml:semantics> </mml:math> protein and the electron transfer from water molecules to the protein <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:semantics><mml:mrow><mml:mtext>⋅⋅⋅</mml:mtext></mml:mrow> <mml:annotation>$\cdots$</mml:annotation></mml:semantics> </mml:math> protein interstitial region. These findings highlight the intrinsic complexity of the CHIKV <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:semantics><mml:mrow><mml:mtext>⋅⋅⋅</mml:mtext></mml:mrow> <mml:annotation>$\cdots$</mml:annotation></mml:semantics> </mml:math> MXRA8 recognition and attachment process in the context of the identified hot spots for protein <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:semantics><mml:mrow><mml:mtext>⋅⋅⋅</mml:mtext></mml:mrow> <mml:annotation>$\cdots$</mml:annotation></mml:semantics> </mml:math> protein interactions. While the persistent interstitial interactions that play relevant roles can be well characterized, their stability and specificity are reinforced by a surrounding cooperative network of non-covalent contacts, including solvent mediated interactions and contributions from neighboring residues and glycans. Together, this dynamic and interconnected interaction network governs viral attachment and stabilizes the protein <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:semantics><mml:mrow><mml:mtext>⋅⋅⋅</mml:mtext></mml:mrow> <mml:annotation>$\cdots$</mml:annotation></mml:semantics> </mml:math> protein binding interface.