Molecular Dynamics Simulation and Free Energy Calculation of Protein Arginine Methyltransferase 1

摘要

Protein arginine methyltransferase 1 (PRMT1) forms S-adenosylhomocysteine (SAH) and arginine by transferring methyl of SAM(S-adenosyl-L-methionine) to the substrate arginine, and then various effects in vivo occur. Our research group designed and synthesized 28 PRMT1 inhibitors which take furan ring as the mother nucleus in earlier stage, this research selected five representative inhibitors and composite of classical known PRMT1 inhibitor AMI1 and PRMT1 for 100 nanoseconds of molecular dynamics simulations to explore the binding modes of these compounds. The research found that these compounds stably bind to the PRMT1 pocket during the entire simulation process, but their binding modes are significantly different from AMI1. AMI1 occupies the binding site of arginine and amino acids, while the small molecule compound occupies the binding site of SAH. Then we used MMPBSA and Nmode to calculate the binding free energy of these small molecules and PRMT1, respectively, and found that the calculated value is positively correlated with the experimental value.