Arginine residues are very important for the structure of proteins and their action. Arginine is essential for many natural processes because it has unique ionizable group under physiological conditions. Numerous mimetics of arginine were synthesized and their biological effects were evaluated, but the mechanisms of actions are still unknown. The aim of this study is to see if oxy- and sulfoanalogues of arginine can be recognized by human arginyl-tRNA synthetase (HArgS)—an enzyme responsible for coupling of L-arginine with its cognate tRNA in a two-step catalytic reaction. We make use of modeling and docking studies of adenylate kinase (ADK) to reveal the effects produced by the incorporation of the arginine mimetics on the structure of ADK and its action. Three analogues of arginine, L-canavanine (Cav), L-norcanavanine (NCav), and L-sulfoarginine (sArg), can be recognized as substrates of HArgS when incorporated in different peptide and protein sequences instead of L-arginine. Mutation in the enzyme active center by arginine mimetics leads to conformational changes, which produce a decrease the rate of the enzyme catalyzed reaction and even a loss of enzymatic action. All these observations could explain the long-lasting nature of the effects of the arginine analogues. 1. Introduction Peptidomimetics have found wide application as bioavailable, biostable, and potent mimetics of naturally occurring biologically active peptides. L-Arginine has guanidinium group, which is positively charged at neutral pH and is involved in many important physiological and pathophysiological processes [1]. It has a very ionizable amino acid, and it is found most frequently buried in the protein interior [2–5]. Arginine residues are essential in a variety of biological processes, such as the regulation of conformation or redox potentials [6, 7]; viral capsid assembly [8]; electrostatic steering [9]; voltage sensing across lipid bilayers [10–12]; H+ transport [6, 13–15] and peptide translocation across bilayers [16, 17]. They also play a critical role at protein-protein interfaces [5, 16], in enzymatic active sites [3, 5, 18], and in variety of transport channels [19, 20]. More recent findings show that arginine-specific methylation of histones may cooperate with other types of posttransitional histone modification to regulate chromatin structure and gene transcription [21]. Proteins that methylate histones on arginine residues can collaborate with other coactivators such as nuclear receptors. Enzymes are probably the most studied biological molecules. They constitute
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