Structural and functional impact of Spike protein mutations in the KP.2 variant

In late 2023, SARS-CoV-2 JN.1 variants were the predominant cause of COVID-19 cases in over 130 countries and territories, classified by the WHO as Variants of Interest (VOI). This JN.1 variant then gave rise to another variant, JN.1.11.1.2, also known as KP.2. KP.2 has unique changes in a part of the virus crucial for entering human cells, called the spike protein. KP.2 had spread quickly to 27 countries and was classified by the WHO as a Variant Under Monitoring (VUM) in April 2024. Our research focused on these changes in the KP.2 spike protein and how they might affect the binding of viruses to human cells. Through sequence analysis, we identified KP.2 as a JN.1 progeny with three distinct mutations: R346T, F456L in the Receptor binding domain (RBD) and V1104L in the S2 subunit. Molecular dynamics simulations revealed that R346T and F456L mutations in the RBD compromise the stability and binding free energy of the KP.2 RBD-hACE2 complex compared to JN.1. Specifically, R346T reduces electrostatic interactions while F456L diminishes van der Waals forces in the KP.2 RBD-hACE2 complex.