Influence of sequential guanidinium methylation on the energetics of the guanidinium...guanine dimer and guanidinium...guanine...cytosine trimer: implications for the control of protein...DNA interactions by arginine methyltransferases

Abstract

Arginine methylation is a post-translational protein modification that is catalyzed by proteins known as arginine methyl transferases (RMTs). Recently, arginine methylation was postulated as an important modification in modulating biomolecular interactions. RMTs largely target nuclear proteins, so it is highly likely that they aid in modulating protein...DNA interactions. In this study, we probe the influence that sequential guanidinium methylation has on the energetics of the guanidinium...guanine and guanidinium...guanine...cytosine complexes using ab initio and double-hybrid density functional theory (DFT) methods. Structures of guanidinium...guanine complexes derived at the MP2/6-31+G** level of theory show that monomethylated, symmetrically dimethylated, and unsymmetrical dimethylated guanidiniums are all capable of forming guanidinium...guanine complexes. However, when cytosine is involved in a base pair to guanine, only the monomethylated and symmetrically dimethylated guanidinium groups are capable of forming hydrogen bond complexes with guanine. At the B2-PLYP/6-311++G** level of theory, we found that methylation of the guanidinium group stabilizes the formation of the guanidinium... guanine complex relative to the unmethylated guanidinium...guanine complex by approximately 2.5 kcal mol(-1). The biological implication of these findings are discussed.

Scheme 1

Figure 1

Hydrogen bonding network formed between the Arg guanidinium group and guanine.

Chart 2

Scheme 2

Figure 2

Geometry optimized structures of the four guanidinium monomers investigated in this study: EG (A), methyl-EG (B), symmetrical dimethyl-EG (C), and unsymmetrical dimethyl-EG (D).

Scheme 3

Scheme 4

Figure 3

Geometry optimized structures for the six guanidinium...guanine dimers examined in this study.

Scheme 5

Figure 4

View of the guanidinium...guanine dimers looking along the xy plane of the guanine. The guanine group is depicted in blue and the guanidinium group is depicted in red.

Figure 5

Geometry optimized structures for the five guanidinium...guanine...cytosine trimers examined in this study.

Figure 6

View of the guanidinium...guanine...cytosine trimers looking along the xy plane of the guanine. The guanine and cytosine groups are depicted in blue and the guanidinium group is depicted in red.