Slow protein evolutionary rates are dictated by surface-core association

摘要

Why do certain proteins evolve much slower than others? We compared not only rates per protein, but also rates per position within individual proteins. For ~90% of proteins, the distribution of positional rates exhibits three peaks: a peak of slow evolving residues, with average Iog_2[normalized rate], log_2μ, of ca. —2, cor responding primarily to core residues; a peak of fast evolving res idues (log_2n ~ 0.5) largely corresponding to surface residues; and a very fast peak (log_2u ~ 2) associated with disordered segments. However, a unique fraction of proteins that evolve very slowly exhibit not only a negligible fast peak, but also a peak with a Iog_2μ～-4, rather than the standard core peak of -2. Thus, a "freeze" of a protein's surface seems to stop core evolution as well. We also observed a much higher fraction of substitutions in poten tially interacting residues than expected by chance, including sub stitutions in pairs of contacting surface-core residues. Overall, the data suggest that accumulation of surface substitutions enables the acceptance of substitutions in core positions. The underlying rea son for slow evolution might therefore be a highly constrained surface due to protein-protein interactions or the need to prevent misfolding or aggregation. If the surface is inaccessible to substitu tions, so becomes the core, thus resulting in very slow overall rates.