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Examining Product Specificity in Protein Arginine Methyltransferase 7 (PRMT7) Using Quantum and Molecular Mechanical

Abhishek Thakur¹, Joan M Hevel², Orlando Acevedo¹

¹Department of Chemistry , University of Miami , Coral Gables , Florida 33146 , United States.

Journal of Chemical Information and Modeling

|April 30, 2019

Abstract:

Protein arginine methyltransferase 7 (PRMT7) catalyzes the formation of monomethylarginine (MMA) but is incapable of performing a dimethylation. Given that PRMT7 performs vital functions in mammalian cells and has been implicated in a variety of diseases, including breast cancer and age-related obesity, elucidating the origin of its strict monomethylation activity is of considerable interest. Three active site residues, Glu172, Phe71, and Gln329, have been reported as particularly important for product specificity and enzymatic activity. To better understand their roles, mixed quantum and molecular mechanical (QM/MM) calculations coupled to molecular dynamics and free energy perturbation theory were carried out for the WT, F71I, and Q329S trypanosomal PRMT7 (TbPRMT7) enzymes bound with S-adenosyl- L-methionine (AdoMet) and an arginine substrate in an unmethylated or methylated form. The Q329S mutation, which experimentally abolished enzymatic activity, was appropriately computed to give an outsized Δ G^‡ of 30.1 kcal/mol for MMA formation compared to 16.9 kcal/mol for WT. The F71I mutation, which has been experimentally shown to convert the enzyme from a type III PRMT into a mixed type I/II capable of forming dimethylated arginine products, yielded a reasonable Δ G^‡ of 21.9 kcal/mol for the second turnover compared to 28.8 kcal/mol in the WT enzyme. Similar active site orientations for both WT and F71I TbPRMT7 allowed Glu172 and Gln329 to better orient the substrate for S_N2 methylation, enhanced the nucleophilicity of the attacking guanidino group by reducing positive charge, and facilitated the binding of the subsequent methylated products.

Insights

Protein arginine methyltransferase 7 (PRMT7) strictly forms monomethylarginine (MMA). Computational studies reveal how active site mutations alter its enzymatic activity and product specificity, offering insights into disease-related functions.

Area of Science:

Biochemistry
Computational Biology
Enzymology

Background:

Protein arginine methyltransferase 7 (PRMT7) is crucial in mammalian cells, with roles in diseases like breast cancer and obesity.
PRMT7's unique ability to catalyze only monomethylation (MMA) is of significant interest.
Specific active site residues (Glu172, Phe71, Gln329) are key to PRMT7's specificity and activity.

Purpose of the Study:

To elucidate the molecular basis of PRMT7's strict monomethylation activity.
To understand the roles of key active site residues (Glu172, Phe71, Gln329) in PRMT7's enzymatic function and product specificity.
To computationally investigate the effects of specific mutations (F71I, Q329S) on PRMT7 activity.

Main Methods:

Mixed quantum and molecular mechanical (QM/MM) calculations.
Molecular dynamics simulations.
Free energy perturbation theory applied to wild-type (WT) and mutant trypanosomal PRMT7 (TbPRMT7) enzymes.

Main Results:

The Q329S mutation, experimentally inactivating the enzyme, showed a significantly elevated free energy of activation (ΔG‡) of 30.1 kcal/mol for MMA formation.
The F71I mutation, experimentally converting PRMT7 to a dimethylating enzyme, yielded a lower ΔG‡ (21.9 kcal/mol) for the second methylation turnover compared to WT (28.8 kcal/mol).
WT and F71I TbPRMT7 exhibited similar active site orientations, facilitating substrate methylation and product binding.

Conclusions:

Computational results align with experimental findings regarding the impact of mutations on PRMT7 activity and specificity.
The study provides a molecular-level understanding of how active site residues dictate PRMT7's catalytic mechanism and product outcome.
Insights gained can inform therapeutic strategies targeting PRMT7 in disease contexts.

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