Context and Force Field
Dependence of the Loss of
Protein Backbone Entropy upon Folding Using Realistic Denatured and
Native State Ensembles
- Publication date
- Publisher
Abstract
The loss of conformational entropy is the largest unfavorable
quantity
affecting a protein’s stability. We calculate the reduction
in the number of backbone conformations upon folding using the distribution
of backbone dihedral angles (ϕ,ψ) obtained from an experimentally
validated denatured state model, along with all-atom simulations for
both the denatured and native states. The average loss of entropy
per residue is <i>T</i>Δ<i>S</i><sup>BB</sup><sub>U–N</sub> = 0.7, 0.9, or 1.1 kcal·mol<sup>–1</sup> at <i>T</i> = 298 K, depending on the force field used,
with a 0.6 kcal·mol<sup>–1</sup> dispersion across the
sequence. The average equates to a decrease of a factor of 3–7
in the number of conformations available per residue (<i>f</i> = Ω<sub>Denatured</sub>/Ω<sub>Native</sub>) or to a
total of <i>f</i><sub>tot</sub> = 3<sup><i>n</i></sup>–7<sup><i>n</i></sup> for an <i>n</i> residue protein. Our value is smaller than most previous estimates
where <i>f</i> = 7–20, that is, our computed <i>T</i>Δ<i>S</i><sup>BB</sup><sub>U–N</sub> is smaller by 10–100 kcal mol<sup>–1</sup> for <i>n</i> = 100. The differences emerge from our use of realistic
native and denatured state ensembles as well as from the inclusion
of accurate local sequence preferences, neighbor effects, and correlated
motions (vibrations), in contrast to some previous studies that invoke
gross assumptions about the entropy in either or both states. We find
that the loss of entropy primarily depends on the local environment
and less on properties of the native state, with the exception of
α-helical residues in some force fields