There are three reaction steps in the S-adenosylmethionine (AdoMet) methylation of lysine-NH2 catalyzed by a methyltransferase. They are (i) combination of enzyme.Lys-NH3+ with AdoMet, (ii) substrate ionization to provide enzyme.AdoMet.Lys-NH2, and (iii) methyl transfer providing enzyme.AdoHcy.Lys-N(Me)H2+ and the dissociation of AdoHcy. In this study of the viral histone methyltransferase (vSET), we find that substrate ionization of vSET.Lys27-NH3+, vSET.Lys27-N(Me)H2+, and vSET.Lys27-N(Me)2H+ takes place upon combination with AdoMet. The presence of a water channel allows dissociation of a proton to the solvent. There is no water channel in the absence of AdoMet. That the formation of a water channel is combined with AdoMet binding was first discovered in our investigation of Rubisco large subunit methyltransferase. Via a quantum mechanics/molecular mechanics (QM/MM) approach, the calculated free energy barrier (DeltaG++) of the first methyl transfer reaction catalyzed by vSET [Lys27-NH2 + AdoMet --> Lys27-N(Me)H2+ + AdoHcy] equals 22.5 +/- 4.3 kcal/mol, which is in excellent agreement with the free energy barrier (21.7 kcal/mol) calculated from the experimental rate constant (0.047 min-1). The calculated DeltaG++ of the second methyl transfer reaction [AdoMet + Lys27-N(Me)H --> AdoHcy + Lys27-N(Me)2H+] at the QM/MM level is 22.6 +/- 3.6 kcal/mol, which is in agreement with the value of 22.4 kcal/mol determined from the experimental rate constant (0.015 min-1). The third methylation [Lys27-N(Me)2 + AdoMet --> Lys27-N(Me)3+ + AdoHcy] is associated with a DeltaG++ of 23.1 +/- 4.0 kcal/mol, which is in agreement with the value of 23.0 kcal/mol determined from the experimental rate constant (0.005 min-1). Our computations establish that the first, second, and third methyl transfer steps catalyzed by vSET are linear SN2 reactions with the bond making being approximately 50% associative.