Arginine methylations can regulate important biological processes and affect many cellular activities, and the enzymes that catalyze the methylations are protein arginine methyltransferases (PRMTs). The biological consequences of arginine methylations depend on the methylation states of arginine that are determined by PRMT’s product specificity. Nevertheless, our understanding is still lacking concerning why different PRMTs may have different ability to direct specific degrees of methylation. Since PRMTs are important targets for drug discovery, the knowledge on product specificity may have important implications for drug discover and for developing strategies for manipulating signaling properties. In this talk, we will focus on PRMT7, the only known member of Type III PRMT that produces mono-methylarginine product (MMA). QM/MM molecular dynamics (MD) and potential of mean force (PMF) free-energy simulations are performed for PRMT7 and its E181D and E181D/Q329A mutants to understand why E181D and E181D/Q329A can catalyze, respectively, the formation of asymmetrically di-methylated arginine (ADMA) and symmetrically di-methylated arginine (SDMA). The computational study have identified some important factors that control the product specificity of PRMT7 and discovered the structural, electronic and dynamic origins that lead to the different product specificities for wild-type PRMT7, E181D and E172D/E181D.

QM/MM investigation of the origins of changing the product specificity from type III arginine methyltransferase into type I and II by specific mutations

ACS Spring 2022

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