(190c) Recovering Single-Molecule Energetics and Kinetics From Force Spectroscopy and Steered Simulations

Understanding how biological molecules and polymers fold into complex 3D structures, bind to each other, and undergo conformational transitions is important from the point of view of designing drugs, dissecting disease mechanisms, designing sensors, and DNA sequencing. Dynamic single molecule force spectroscopy provides a powerful approach for probing the underlying energy landscape governing such molecular processes. These sophisticated experiments operate by imposing gradually increasing forces on the molecular system being probed and recording its force-extension behavior until eventual rupture. An outstanding question in this field is how to recover the intrinsic energy landscape of the molecular system from such force measurements. In this talk I will describe the development of new theoretical models for extracting the height and location of activation energy barriers and intrinsic transition rates from single-molecule force measurements [1,2]. The models go beyond the current state-of-the-art by accounting for both the finite stiffness of the pulling device and the non-linear stretching of the polymeric handles often used for connecting the molecule of interest to the device. I will also discuss our recent efforts in combining such theoretical models with steered molecular dynamics simulations for computing the stability of secondary structures in proteins and the binding free energies of drugs molecules [3].

[1] Maitra and Arya, “Model accounting for the effects of pulling-device stiffness in the analyses of single-molecule force measurements,” Phys. Rev. Lett., 104, 108301, 2010

[2] Maitra and Arya, “Influence of pulling handles and device stiffness in single-molecule force spectroscopy,” Phys. Chem. Chem. Phys., 13, 1836, 2011

[3] Meluzzi, Maitra, and Arya, in preparation.