Lattice models, packing density, and Boltzmann-like distribution of cavities in proteins

A model reproducing the experimental Boltzmann‐like distribution of empty cavity sizes in proteins is introduced. Proteins are represented by lattices of different dimensionalities, corresponding to different numbers of nearest neighbor contacts. Small cavities emerge and join into larger ones in a random process that can be related to random mutations. Simulations of cavity creation are performed under the constraint of a limiting total packing density. Cavities sufficiently large (20 Å3 or more), that they might accommodate at least one additional methyl group produced by a mutation, are counted and compared to the distribution of cavities according to their sizes from protein statistics. The distributions calculated with this very simple model within a realistic range of packing densities are in good agreement with the empirical cavity distribution. The results suggest that the Boltzmann‐like distribution of cavities in proteins might be affected by a mechanism controlled by limiting packing density and maximum allowed protein destabilization. This supports an earlier suggestion that the agreement between the free energies of cavity formation from the mutational experiments and from the statistics of the empty cavity distribution in X‐ray protein structures is nonfortuitous. A possible relation of the suggested model to the Boltzmann hypothesis is discussed. Proteins 2005. © 2004 Wiley‐Liss, Inc.