Computational Study of Symmetric Methylation on Histone Arginine Catalyzed by Protein Arginine Methyltransferase PRMT5 through QM/MM MD and Free Energy Simulations.

Yufei Yue,Yuzhuo Chu,Hong Guo

doi:10.3390/molecules200610032

Abstract

Protein arginine methyltransferases (PRMTs) catalyze the transfer of the methyl group from S-adenosyl-l-methionine (AdoMet) to arginine residues. There are three types of PRMTs (I, II and III) that produce different methylation products, including asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and monomethylarginine (MMA). Since these different methylations can lead to different biological consequences, understanding the origin of product specificity of PRMTs is of considerable interest. In this article, the quantum mechanical/molecular mechanical (QM/MM) molecular dynamics (MD) and free energy simulations are performed to study SDMA catalyzed by the Type II PRMT5 on the basis of experimental observation that the dimethylated product is generated through a distributive fashion. The simulations have identified some important interactions and proton transfers during the catalysis. Similar to the cases involving Type I PRMTs, a conserved Glu residue (Glu435) in PRMT5 is suggested to function as general base catalyst based on the result of the simulations. Moreover, our results show that PRMT5 has an energetic preference for the first methylation on Nη1 followed by the second methylation on a different ω-guanidino nitrogen of arginine (Nη2).The first and second methyl transfers are estimated to have free energy barriers of 19–20 and 18–19 kcal/mol respectively. The computer simulations suggest a distinctive catalytic mechanism of symmetric dimethylation that seems to be different from asymmetric dimethylation.

Highlights

Posttranslational methylation of histone proteins on their arginine residues is an epigenetic mark that plays a vital role in cell function and is related with cell disorders and diseases [1]
F327, K333, S578 and S439 in PRMT5 are the conserved residues among Type-II Protein arginine methyltransferases (PRMTs)
In the active site of the PRMT5 structure (Figure 1A), Nη1 appears to be in a much better position for acting as the methyl acceptor compared to Nη2; this is in contrast with the case of PRMT3 where Nη2 seems to be in a better position for accepting the methyl group [26]

Summary

Introduction

Posttranslational methylation of histone proteins on their arginine residues is an epigenetic mark that plays a vital role in cell function and is related with cell disorders and diseases [1]. Depending on types of PRMTs (I, II or III), the methylation products may contain asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) or monomethylarginine (MMA) (shown in Scheme 1) [1]. Methylation of arginine by different types of PRMTs. Type I PRMT can produce both monomethylarginine (MMA) and asymmetric dimethylarginine (ADMA). The Type II PRMT5 to be investigated in this work catalyzes the transfer of methyl groups to the two different ω-guanidino nitrogen atoms on the arginine residue of the target protein, producing the ω-NG, N′G symmetrically dimethylated arginine (SDMA) [4]. The computational approaches used in these earlier studies include molecular dynamics and free energy simulations (potential of mean force) with the hybrid quantum mechanical and molecular mechanical (QM/MM) potential that seem to be suitable to investigate the enzyme-catalyzed methyl transfer process and have been widely used for some other methyltransferases [26,27,28,29,30,31,32]. Our computational study provides a better understanding of the symmetric di-methylation mechanism that is different from the asymmetric di-methylation

Comparison of the Active Site Structures of Type II PRMT5 and Type I PRMT3

The First Methylation Catalyzed by PRMT5

The Second Methylation Catalyzed by PRMT5

Experimental Section

Conclusions