BioSystems. 8 (1977) 185-186 @ ElsevierlNorth-Holland Scientific Publishers, Ltd. QNSAGER COUPLING IN ENZYMES * G. CARERI and E. GRATTON Zstituto di Fisica. Universitci di Roma, (Received Italy January 17th. 1977) In a conference at Coral Gables in Novem- ber 1973, on the occasion of the seventieth birthday of Lars Onsager, one of us, Careri (1974), proposed a mechanism of enzyme action grounded on the capability of the enzyme to correlate in time the statistical fluctuations of some macrovariables relevant for catalysis. This property can be expressed by a non-vanishing Qnsager matrix, and Lars Onsager was very pleased with this picture because the enzymes being catalysts must work reversibly around equilibriu said the “Onsager approximation” to hold in this case. As a result of Lars Onsager’s eneourage- ment, the statistical time events which occur in enzymes have been critically reviewed by Careri et al. (1975) and the presence of nano- second fluctuations in a dry lysozyme pow- der has been proved by oxygen quenching by Careri, .Gratton in the experiment ed). ‘This experimental and Weber (unpub f spontaneous fhc- fact implies the ex tuations also in the active site of the enzyme, and, together with the known stochastic nature of the solvation effects, allow us to propose here an oversimplified model of the enzymatic action using one term of the Onsager matrix only, as follows. dig all the biochemical consider- ut the stepwis energy barrier the system must receive some free energy from the surrounding bath, and let us assume that this can be accomplished by a fluctuation. Molecular considerations not to be reviewed here, led to the conclusion that the major process by which the free energy can be exchanged between the macro- molecule and the bath must be identified in the accommodation and release of the water molecules bound on the backbone amide groups which are accessible to the solvent. This bound water is known to amount up to ZO-30% in weight of the macromJecule itself. Since theginding of the water molecule to the amide group increases the polar char- acter of the peptide bond, and this induces a change in its conformation because of the increased planarity of the amide group, there is a possible propagation of these conforma- tional changes from the surface of the enzyme to its active site, where even subtle conforma- tional changes are essential to lower the free energy profile of the chemical reaction. Therefore a fluctuation of the bound water density at the surface can be coupled with a spont~eous confo~ati~~~ ~u~t~~t~on at the antive core, and this statistical cou can be expressed by a non-vanis coefficient, when the two stati ely that in order to o reaction coor * Invited paper. Dedicated to the ~e~~~ Onsager. ** Permanent address: Laboratorio Ricer&e onterotondo, Roma, Italy. of Lark di Base,