Electrostatic and Allosteric Response of Myosin upon ATP Binding

Abstract

Protein molecules regulate their biological functions utilizing allostery, and underlying physical mechanisms of allostery have long been studied. While a large-scale seesaw-like structure change upon ligand binding is often noticed, the allosteric mechanism that does not exhibit such rigid-body-like tertiary structural change has recently received much attention. In this study, we report on an allosteric mechanism that is not due to the large-scale tertiary structure change but is due to the intrinsic dielectric property of the protein molecule. We conducted molecular dynamics simulations of myosin, a well-known motor protein with allostery, and investigated the response to ATP binding. ATP binding is a crucial step in the force-generating cycle, causing myosin to dissociate from the actin filament and pushing forward the cycle. We found that the negative net charge of ATP causes large-scale dielectric responses in myosin, which induces the polarization charge and resulting electrostatic potential change in the distant actin-binding region. Furthermore, this potential change moves the positively-charged actin-binding loop apart from actin. The observed dielectric response is mainly due to the orientational change of the charged/polar residues: the residues near the ATP phosphates respond fast, which propagates to the surface on the slower time scale. Our finding indicates the important role of the dielectric and electrostatic properties of myosin in allosterically regulating the force-generating actin-myosin binding, further suggesting that the dielectric allostery has a general importance in a wide range of biological functions of allosteric proteins.