Steered Molecular Dynamics Simulations of Inner-Ear Cadherins using the Drude Polarizable Force Field

Abstract

Steered molecular dynamics (SMD) simulations have provided invaluable insights into the unbinding and unfolding mechanisms of proteins with mechanical function. In the case of tip link cadherins involved in inner-ear mechanotransduction, SMD simulations have revealed possible unbinding and unfolding pathways, showed how structural elements and calcium ions are essential for rigidity and unfolding strength, and predicted unbinding and unfolding forces that are relevant at the physiological, fast time scales of sound transduction. Yet all these simulations have used classical force fields that do not take into account atomic polarizability, which is critical for the accurate description of interactions between divalent ions and charged protein side chains. Here, we present SMD simulations of the calcium-dependent cadherin-23 and protocadherin-15 interaction that test the effect of atomic polarizability on its dynamics and mechanical strength. We compared parallel simulations that used either the fixed-atomic charge additive CHARMM36 or the Drude polarizable force fields. A variety of pulling speeds and simulation protocols were tested as well. These simulations shed light on the importance of polarizability on the calcium-dependent mechanics of tip link cadherins.