Abstract
The mechanics of the actomyosin interaction is central in muscle contraction and intracellular trafficking. A better understanding of the events occurring in the actomyosin complex requires the examination of all nucleotide-dependent states and of the energetic features associated with the dynamics of the cross-bridge cycle. The aim of the present study is to estimate the interaction strength between myosin in nucleotide-free, ATP, ADP·Pi and ADP states and actin monomer. The molecular models of the complexes were constructed based on cryo-electron microscopy maps and the interaction properties were estimated by means of a molecular dynamics approach, which simulate the unbinding of the complex applying a virtual spring to the core of myosin protein. Our results suggest that during an ATP hydrolysis cycle the affinity of myosin for actin is modulated by the presence and nature of the nucleotide in the active site of the myosin motor domain. When performing unbinding simulations with a pulling rate of 0.001 nm/ps, the maximum pulling force applied to the myosin during the experiment is about 1nN. Under these conditions the interaction force between myosin and actin monomer decreases from 0.83 nN in the nucleotide-free state to 0.27 nN in the ATP state, and increases to 0.60 nN after ATP hydrolysis and Pi release from the complex (ADP state).
Highlights
Myosins are molecular motors which interact with actin filaments and employ energy from ATP hydrolysis to provide conformational changes, which generate force
A first approximation of the atomic model of the actomyosin complex can be obtained by fitting the atomic structures of actin and myosin motor domain into three-dimensional cryoelectron microscopy maps of decorated actin [19]
In order to address this issue, we propose a new approach based on molecular dynamics (MD) to evaluate the interaction properties of the actomyosin complex
Summary
Myosins are molecular motors which interact with actin filaments and employ energy from ATP hydrolysis to provide conformational changes, which generate force. Three-dimensional structures of both myosin and actin have been recently solved by high resolution X-ray crystallography. The actin molecule, which is the myosin substrate, has been solved too; atomic models of a single rabbit actin monomer [14, 15] complexed with gelsolin [16, 17] or DNase 1 [18] are available. All crystallographic models of myosin in different nucleotide binding states were obtained in absence of actin, since a co-crystallization seems still impossible to achieve. A first approximation of the atomic model of the actomyosin complex can be obtained by fitting the atomic structures of actin and myosin motor domain into three-dimensional cryoelectron microscopy maps of decorated actin [19]
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