Buried and accessible surface area control intrinsic protein flexibility

TL;DR

This paper demonstrates that a protein's intrinsic flexibility is closely linked to the amount of surface area buried within its structure, and introduces a simple method to predict flexibility from structural data.

Contribution

It reveals the relationship between buried surface area and protein flexibility and proposes a practical proxy for predicting flexibility from 3D structures.

Findings

Relative solvent accessible surface area correlates with global protein flexibility.

Flexibility is associated with multiple domains and increased alpha-helical content.

More flexible proteins tend to have lower-resolution crystal structures.

Abstract

Proteins experience a wide variety of conformational dynamics that can be crucial for facilitating their diverse functions. How is the intrinsic flexibility required for these motions encoded in their three-dimensional structures? Here, the overall flexibility of a protein is demonstrated to be tightly coupled to the total amount of surface area buried within its fold. A simple proxy for this, the relative solvent accessible surface area (Arel), therefore shows excellent agreement with independent measures of global protein flexibility derived from various experimental and computational methods. Application of Arel on a large scale demonstrates its utility by revealing unique sequence and structural properties associated with intrinsic flexibility. In particular, flexibility as measured by Arel shows little correspondence with intrinsic disorder, but instead tends to be associated with multiple domains and increased {\alpha}- helical structure. Furthermore, the apparent flexibility of monomeric proteins is found to be useful for identifying quaternary structure errors in published crystal structures. There is also a strong tendency for the crystal structures of more flexible proteins to be solved to lower resolutions. Finally, local solvent accessibility is shown to be a primary determinant of local residue flexibility. Overall this work provides both fundamental mechanistic insight into the origin of protein flexibility and a simple, practical method for predicting flexibility from protein structures.