Molecular Dynamics Study of Talin-Vinculin Binding

Abstract

Cells can sense mechanical force in regulating focal adhesion assembly. One vivid example is the force-induced recruitment of vinculin to reinforce initial contacts between a cell and the extracellular matrix. Crystal structures of the unbound proteins and bound complex between the vinculin head subdomain (Vh1) and the talin vinculin binding site 1 (VBS1) indicate that vinculin undergoes a conformational change upon binding to talin. However, the molecular basis for this event and the precise nature of the binding pathway remain elusive. In this article, molecular dynamics is used to investigate the binding mechanism of Vh1 and VBS1 under minimal constraints to facilitate binding. One simulation demonstrates binding of the two molecules in the complete absence of external force. VBS1 makes early hydrophobic contact with Vh1 by positioning the critical hydrophobic residues (L608, L615, and L622) in the groove formed by helices 1 and 2 of Vh1. The solvent-exposed hydrophobic residues (V619 and L623) then gradually penetrate the hydrophobic core of Vh1, thus further separating helix 1 from helix 2. These critical residues are highly conserved as large hydrophobic side groups in other vinculin binding sites; studies also have demonstrated that these residues are essential in Vh1-VBS1 binding. Similar binding mechanisms are also demonstrated in separate molecular dynamics simulations of Vh1 binding to other vinculin binding sites both in talin and alpha-actinin.

The heel and toe of the cell's foot: A multifaceted approach for understanding the structure and dynamics of focal adhesions

“…There are several sites on the talin rod that bind the vinculin head [Ziegler et al, 2008]. The majority of these sites are cryptic (buried inside the rod), but can be opened by unfolding the talin molecule, as was proposed in structural studies [Fillingham et al, 2005; Gingras et al, 2006; Papagrigoriou et al, 2004], verified by steered molecular dynamic simulations [Hytonen and Vogel, 2008 ; Lee et al, 2007, 2008], and finally directly demonstrated in experiments involving the stretching of talin rods in vitro [del Rio et al, 2009]. Notably, binding of the vinculin head to talin promotes binding of the vinculin tail to the actin filament [Bois et al, 2006].…”

Multiscale mechanobiology: computational models for integrating molecules to multicellular systems

“…3 Altered conformations of the tandem repeats may trigger downstream signaling cascades, for instance by modulating binding to filamin interacting protein and downstream pathways. 3 Furthermore, phosphorylation of filamin A at Ser 21,52 appears to promote force-induced unfolding and affinity for integrin. 18 A recent single-molecule experiment with optical tweezers on filamin A showed another potential mechanism for mechanosensing based on force-induced cis–trans proline isomerization of the force sensing domain pair 20–21 in filamin A.…”

Molecular Biomechanics: The Molecular Basis of How Forces Regulate Cellular Function

“…Specifically, it is important to characterize how the three-dimensional structural rigidity of DNA, RNA and proteins control their deformation under various loading conditions—stretching, twisting, bending and shear conditions—and how such deformation alters DNA condensation, gene replication and transcription, DNA–protein/RNA–protein interactions, protein function, protein–protein interaction, and protein–ligand interaction 5–7,14,48,51,53,71. These research topics encompass bond formation, reaction rates, and the thermodynamics and kinetics of biomolecular interactions.…”

“…To date, the molecular mechanisms of force sensing and mechanotransduction remain elusive. While numerous mechanisms have been proposed, a strong candidate for the molecular mechanism of mechanosensing and mechanotransduction is protein deformation, or protein conformational change under force 41,51,53,87,95,96. The unique three-dimensional structure (i.e., conformation) of a protein largely determines its function.…”