Source:  (article, 2024-09-19)
Field: Chemistry — Physical and Theoretical Chemistry

Calculating of SARS-CoV-2 RBD and antibody complex energy by metadynamics in MARTINI 3 for evaluating complex free energy Motivation and Aim: Neutralizing monoclonal antibodies (MAbs) have been found to be effective therapeutic agents in the treatment of a host of viral and autoimmune diseases.This has been particularly highlighted since the outbreak of the 2019 coronavirus infection (COVID-19), which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).In response to this global health crisis, the Food and Drug Administration (FDA) has given its approval to several drugs that are based on MAbs [1].The emergence of new variants of the virus has presented a significant hurdle in the ongoing fight against COVID-19.Some of these variants have shown resistance to the existing neutralizing MAbs, reducing their overall efficacy [2].There's an urgent need for new strategies for rapid antibody design to respond to emerging variants and maintain our therapeutic effectiveness.Nowadays, there is a rising trend towards the utilization of diffusion machine learning models in the field of the design of innovative protein sequences [3].These advanced models allow for the intricate redesigning of the antibody constant determining regions (CDR) loops.This is a significant step in the field as it enables us to specifically tailor these CDR loops to correspond with the antigen epitope we require.To improve the design results and antibody affinity to antigen, we must have initial stable structures of the antigen antibody complex, in which the antibody will target different epitopes.These states can be obtained by the methods of molecular dynamics.One of them, rapid and effective metadynamics, allows one to quickly and efficiently scan different states of a system by adding Gaussian potentials to local free energy minima during a trajectory [4].Adding to this, representation of structures in the Martini force field together with the use of metadynamics speeds up FES calculations for proteinprotein complexes [5].Therefore, using the metadynamics method in MARTINI 3 atoms representation can allow us to estimate and range hundreds of results of structures obtained from generative diffusion models.In this report, we detail the application of metadynamics to the most common antibody and SARS-CoV-2 RBD in the Martini 3 force field.We initially created two complexes where the antibody targets the two most likely neutralizing receptor binding domain epitopes.We then performed metadynamics on each complex and identified the states corresponding to the free energy minima.Methods and Algorithms: SARS-Cov-2 neutralizing MAbs targeted to SARS-CoV-2 Sprotein RBD data were downloaded from The Coronavirus Antibody Database CoV-AbDab [6].Based on them, two antibody-antigen complexes were constructed, in which Metadynamics ; Energy (signal processing) ; Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ; Computer science ; Coronavirus disease 2019 (COVID-19) ; Physics ; Chemistry ; Molecular dynamics ; Medicine ; Computational chemistry ; Quantum mechanics thermodynamics and calorimetric analyses ; Mathematical Biology Tumor Growth ; Radioactive Decay and Measurement Techniques