Excluded volume as a determinant of macromolecular structure and reactivity

Abstract

SynopsisThe effect of excluded volume on the thermodynamic activity of globular macromolecules and macromolecular complexes in solution is studied in the hard-particle approximation. Activity coefficients are calculated as a function of the fraction of total volume occupied by macromolecules using relations obtained from scaled particle and lattice models. Significant and readily observable effects are predicted to occur as the fraction of volume occupied by globular macromolecules increases, including the following: (i) Compact quasi-spherical macromolecular conformations become increasingly energetically favored over extended anisometric conformations. (ii) Self-and heteroassociation processes are enhanced, particularly those leading to the formation of compact quasi-spherical aggregates. (iii) Depending upon the details of the reaction mechanism, the rate of an enzyme-catalyzed reaction may monotonically decrease, go through a maximum, or exhibit more complex behavior. A given degree of volume occupancy by larger macromolecules is predicted to have less effect on the structure and self-association of smaller macromolecules than the same degree of volume occupancy by smaller macromolecules has on the structure and self-association of larger macromolecules. INTRODUCTIONThe kinetics and equilibria of biochemical reactions are typically studied in solutions in which all macromolecular species are dilute. Many physiological media, however, have substantial macromolecular content. For example, protein comprises about 5% (by weight) of lymph, about 9% of blood plasma, and about 35% of hemo1ysate.l A medium such as cytosol may contain no single macromolecular species at high concentration, yet taken together the mobile macromolecular species occupy a substantial volume fraction of the medium. All of these media may be generally described as volume-occupied. We shall use the term concentrated in a more restricted sense to describe a medium in which the particular species of interest is (or are) present at high concentration.The degree to which a medium is volume-occupied may affect biochemical equilibria and kinetics in a variety of ways, due to the many types of interactions which can exist between macromolecules. The purpose of the present work is to demonstrate that even in the absence of direct interactions between macromolecular species, the volume from which macromolecules are excluded by other macromolecules can have a profound Biopolymers, Vol. 20,2093-2120 A brief model-independent treatment of the effect of nonideal behavior on thermodynamic equilibria, and by extension (via transition-state theory) on kinetics, is presented below. Two approximate methods used to calculate the effect of excluded volume on thermodynamic activity are described and the effect of excluded volume on conformational equilibria is treated. The effects of excluded volume on macromolecular self-association and on the kinetics of model enzyme-catalyzed reactions, are discussed. Possible biological ramifications of the excluded-volume e...

Soft interactions and crowding

“…If both particles are spheres, the hard-core excluded volume equals the co-volume; the volume of a sphere whose radius is the sum of the crowder and protein radii (Winzor and Wills 1995). Excluded volume arising from hard-core repulsion also increases with crowder size and concentration (Minton 1981).…”

“…Scaled particle theory allows assessment of nonideality for any hard convex particle in the midst of similarly shaped but differently sized hard particles (Lebowitz et al 1965;Reiss 1966). Lattice theory, on the other hand, approximates the non-ideality of a hard particle of any shape in the midst of hard rectangular parallelepipeds (Minton 1981).…”

“…This stabilizing effect is completely entropic because the model involves only the arrangement of molecules, not chemical interactions between them. Minton (1981) was the first to fully describe these ideas in terms of biology. Later, Zhou et al (2008) also considered the equilibrium effects of crowding and confinement on biomolecular association, ligand binding, and protein stability with emphasis on steric, hard-core repulsions.…”

“…Part of the entropic contribution under crowded conditions arises from steric hard-core repulsions between the crowding molecules and the test protein. As pointed out by Minton (1981) in his ground-breaking work, these steric interactions are predicted to increase stability because N is more compact than D. Until recently, most efforts to understand crowding effects have focused on this entropic component.…”

Population dynamics, information transfer, and spatial organization in a chemical reaction network under spatial confinement and crowding conditions

“…They often contain autocatalytic steps [5][6][7][8][9] and their dynamics tends to be strongly influenced by thermal and intrinsic noise 10,11 , macromolecular crowding and spatial confinement [12][13][14][15][16] . In this study we present a simple computational model of a generic biochemical network in vivo and we investigate how its dynamics is affected by spatial confinement and particle crowding.…”