Hypervariability of accessible and inaccessible conformational space of proteins

Abstract

Proteins undergo motions in a range of amplitudes, from domain motions to backbone rotations, leading to changes in (φ,ψ) torsion angles and small-scale bond vibrations and angle bending. Here, we study the extent of variations in (φ,ψ) values in proteins and the effects of bond geometry variations due to vibrational motions in a protein on the accessible, (steric clash-free) (φ,ψ) space. We perform 1-fs timestep unconstrained molecular dynamics simulations on super-high-resolution protein structures. Extent of variations in bond geometry during the simulation is within acceptable ranges of bond lengths and angles. However, the steric clash-free (φ,ψ) space continuously changes as seen in bond geometry-specific (φ,ψ) steric maps at the residue level during simulations. (φ,ψ) regions that have steric clash at one timepoint can become steric clash-free at a different timepoint through minor adjustments to backbone bond lengths and angles. Also instances of (φ,ψ) transitions from the left to right half of the (φ,ψ) map in consecutive snapshots of the trajectory are seen. Although the two quadrants are separated by a steric clash-prone region, corresponding to a high-energy barrier, height of this barrier is lowered by adjusting the bond geometry such that a bridging region of steric clash-free, low-energy (φ,ψ) values is formed. We demonstrate the idea of dynamically varying nature of acceptable and accessible (φ,ψ) steric space in proteins, which has implications for protein folding; proteins could sample (φ,ψ) space which is originally considered to be inaccessible, during folding, through minor adjustments to their backbone bond geometry.