CHEMIOSMOTIC ATPase MECHANISMS Peter Mitchell Clynn Research Institute Bodmin, Cornwall, PL30 zyxw 4AU, England Willem H. Koppenol Department of Chemistry University of Maryland Baltimore County Catonsville, Maryland 21228 zyxw Our main aim in this paper on the ion-motive ATPases is to comment on some realistic theoretical molecular models that may possibly be used to stimulate and guide experimental research into the molecular structure and function of these remarkable osmoenzymes (for reviews, see References 1-30). For reasons that have become increasingly relevant with the growth of knowledge of the detailed topology of biochemical systems over the last 25 year^,^^.^' we take the view that much better progress may be made on the basis of a biomechanical formality, in which we treat the ATPase molecules as miniature statistical-mechanical engines or machine^,^'.^^ than on the customary basis of a bioenergetic formality, which has encouraged us to regard the ATPase molecules as protein black boxes that can do anything thermodynamically feasible by appropriate conformatiopal prestidi- gitation, the secrets of which are not intended to be visible to the onlooker^.'^^^^ At the risk of spoiling the fun, we suggest that the conjuring bioenergetic fingers may be revealed by focusing attention on the balance of real interatomic vectorial forces that cause the relative motions of the chemical groups and ions involved in the ion-motive ATPase mechanism^.^^'^^,^^,^^ In the chemiosmotic processes catalyzed by the ion-motive ATPases, the reversible coupling between the chemical group-transfer process of ATP hydroly- sis in the catalytic site domain and the osmotic process of ion translocation through the osmotic barrier domain in the osmoenzyme molecules may be abstractly accounted for by the balance of chemical and osmotic energy changes, according to the first law of thermodynamics. Thus, at equilibrium, the sum of the chemical and osmotic energy changes is zero. However, the abstract [scalar) energy changes are given by multiplying the vectorial forces on the chemical particles involved in the osmoenzyme-catalyzed process [including mobile com- ponents of the osmoenzyme molecule) by the colinear vectorial displacements that these particles undergo as the system turns over through its working catalytic configurational cycle, like a miniature engine.28.29.s6.37 The equilibrium condition of energy balance can accordingly be seen as a consequence of what we call the first law of molecular mechanics-the essentialIy Newtonian statistical-mechani- cal principle that the forces of action and reaction on every particle are equal and opposite.” In other words, the sum of the vectorial chemical and osmotic forces on each of the chemical groups and ions involved in the chemiosmotic process must be zer0?5,37 These considerations lead us to ask explicitly: What is the magnitude of the forces that must be transmitted between the chemical groups undergoing transfer and the ions undergoing translocation in the ion-motive ATPase molecules? And by what means, and how directly, are these forces transmitted? zyx 584 0077-8923/82/0402-0584 $01.75/0 zyxwvu 0 1982. NYAS