Toward a molecular understanding of the anisotropic response of proteins to external forces: Insights from elastic network models

¹ University of Pittsburgh

^* To whom correspondence should be addressed. E-mail: bahar{at}pitt.edu.

Submitted on August 27, 2007
Revised on October 2, 2007
Accepted on 18 December 2007

	Abstract

With recent advances in single molecule manipulation techniques, it is now possible to measure the mechanical resistance of proteins to external pulling forces applied at specific positions. Remarkably, such recent studies demonstrated that pulling/stretching forces required to initiate unfolding vary considerably depending on the location of application of the forces, unraveling residue/position-specific response of proteins to uniaxial tension. Here we show that coarse-grained elastic network models based on the topology of inter-residue contacts in the native state can satisfactory explain the relative sizes of such stretching forces exerted on different residue pairs. Despite their simplicity, such models presumably capture a fundamental property that dominates the observed behavior: deformations that can be accommodated by the relatively lower frequency modes of motions intrinsically favored by the structure require weaker forces, and vice versa. The mechanical response of proteins to external stress is therefore shown to correlate with the anisotropic fluctuation dynamics intrinsically accessible in the folded state. The dependence on the overall fold implies that evolutionarily related proteins sharing common structural features tend to possess similar mechanical properties. However, the theory cannot explain the differences observed in a number of structurally similar but sequentially distant domain, such as the fibronectin domains.

Key Words: AFM, ANM, Mecahnical Response, Normal Mode Analysis, Protein Unfolding