Hybrid QM/MM Simulations of Phosphorilation Reactions in PPARg

• Grant number: 25/11647-2
• Support Opportunities: Scholarships in Brazil - Master
• Start date: September 01, 2025
• End date: August 31, 2026
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Physical-Chemistry
• Principal Investigator: Munir Salomao Skaf
• Grantee: Matheus José Novais Landim
• Host Institution: Instituto de Química (IQ). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 13/08293-7 - CCES - Center for Computational Engineering and Sciences, AP.CEPID

Abstract

Nuclear receptors (NRs) comprise a very important superfamily of proteins that regulate transcription of genes which play pivotal roles both in development and adult homeostasis. Among the nuclear receptors, the Peroxisome Proliferator-Activated Receptors (PPARs) - subtypes alpha, beta/delta, and gamma - have received a great deal of attention because of their involvement in glucose and lipid metabolism, apart from being also involved in inflammatory and immune responses. The PPARs play key roles in the so-called 'modern diseases' - such as type II diabetes, obesity, dyslipidemia, and vascular diseases - being attractive targets to the pharmaceutical industry. An alternative regulatory mechanisms within the NR superfamily was published a decade ago in what is today considered a breakthrough study revealing that phosphorylation of PPARg by a cyclin dependent kinase 5 (Cdk5) changes the pattern of genes that are expressed without affecting PPAR³ activity in vitro - i.e. the ability of PPARg to recruit coactivator proteins. The phosphorylation site is located near the sub-pocket occupied by partial agonists, which have also been proven capable of preventing phosphorylation by Cdk5, thus enhancing the expression of genes related to insulin sensitizing effects while decreasing the expression of those related to insulin resistance and adipogenesis. Here, we propose carrying out in silico studies of the binding of partial agonists to PPARg and to investigate their ability of inhibiting phosphorylation by Cdk5 by means of hybrid quantum mechanics/molecular mechanics (QM/MM) molecular dynamics (MD) simulations. The strategy involves: 1) docking several different types of ligands into PPARg to understand the molecular basis that make each ligand to behave as full agonist, partial agonist, antagonist, and/or phosphorylation inhibitor, followed by 2) extensive MD simulations to evaluate ligand-protein binding affinity, 3) refinement of the PPARg-Cdk5 (protein-protein) binding structure using artificial intelligence techniques, and 4) performing a detailed analysis of the phosphorylation reaction itinerary and the associated free energy landscape using state-of-the-art QM/MM methods. (AU)