Enhanced Sampling Molecular Dynamics to Determine Force Response in Peptide Tension Sensors

Abstract

Mechanical forces are prevalent in diverse cellular processes, such as cell division, motility and adhesion. “Mechanoresponsive” proteins are present which respond to these applied forces by changing their structure to perform some function. Scientists have developed Tension Sensing modules to determine the size and location of forces associated with Mechanoresponsive protein assemblies such as Focal Adhesions complexes. However, it is not well understood why certain peptides are better suited to be tension sensors nor in general how to predict mechanical properties from sequence. As a consequence, it is not clear why different tensions sensors are optimally responsive in different force regimes. Current experimental approaches to study piconewton (pN) forces such as single force microscopy are often difficult to implement to study changes under such small forces. However, Molecular Dynamics (MD) and Enhanced sampling techniques can be used to study the effect of applied forces on peptides at the molecular level. Here we will present our work to develop methodologies that can rapidly predict the force-extension behavior of small peptides, and show our recent developments that will allow us to predict the behavior of full-length tension sensing peptide modules.