Conformational Strain Indicated by Ramachandran Angles for the Protein Backbone Is Only Weakly Related to the Flexibility

Studies
on energy associated with free dipeptides have shown that
conformers with unfavorable (ϕ,ψ) torsion angles have
higher energy compared to conformers with favorable (ϕ,ψ)
angles. It is expected that higher energy confers higher dynamics
and flexibility to that part of the protein. Here, we explore a potential
relationship between conformational strain in a residue due to unfavorable
(ϕ,ψ) angles and its flexibility and dynamics in the context
of protein structures. We compared flexibility of strained and relaxed
residues, which are recognized based on outlier/allowed and favorable
(ϕ,ψ) angles respectively, using normal-mode analysis
(NMA). We also performed in-depth analysis on flexibility and dynamics
at catalytic residues in protein kinases, which exhibit different
strain status in different kinase structures using NMA and molecular
dynamics simulations. We underline that strain of a residue, as defined
by backbone torsion angles, is almost unrelated to the flexibility
and dynamics associated with it. Even the overall trend observed among
all high-resolution structures in which relaxed residues tend to have
slightly higher flexibility than strained residues is counterintuitive.
Consequently, we propose that identifying strained residues based
on (ϕ,ψ) values is not an effective way to recognize energetic
strain in protein structures.