Abstract
Molecular simulations of the forced unfolding and refolding of biomolecules or molecular complexes allow to gain important kinetic, structural and thermodynamic information about the folding process and the underlying energy landscape. In force probe molecular dynamics (FPMD) simulations, one pulls one end of the molecule with a constant velocity in order to induce the relevant conformational transitions. Since the extended configuration of the system has to fit into the simulation box together with the solvent such simulations are very time consuming. Here, we apply a hybrid scheme in which the solute is treated with atomistic resolution and the solvent molecules far away from the solute are described in a coarse-grained manner. We use the adaptive resolution scheme (AdResS) that has very successfully been applied to various examples of equilibrium simulations. We perform FPMD simulations using AdResS on a well studied system, a dimer formed from mechanically interlocked calixarene capsules. The results of the multiscale simulations are compared to all-atom simulations of the identical system and we observe that the size of the region in which atomistic resolution is required depends on the pulling velocity, i.e. the particular non-equilibrium situation. For large pulling velocities a larger all atom region is required. Our results show that multiscale simulations can be applied also in the strong non-equilibrium situations that the system experiences in FPMD simulations.
Highlights
Force spectroscopy is a standard experimental technique to investigate unfolding pathways, details of the energy landscape and the mechanical properties of single biomolecules and molecular complexes[1, 2, 3]
We used a box of size of (7.49 nm)3 for all AA simulations and the adaptive resolution scheme (AdResS) simulations we have found in earlier studies of the calix[4]arene catenane dimer system that a box length of 5.8 nm is sufficient for all force probe molecular dynamics (FPMD) simulations performed so far[36, 37]
We have presented a detailed investigation of the applicability of the AdResS methodology to FPMD simulations
Summary
Force spectroscopy is a standard experimental technique to investigate unfolding pathways, details of the energy landscape and the mechanical properties of single biomolecules and molecular complexes[1, 2, 3]. In order to speed up FPMD simulations, some of the well established techniques of coarse graining have successfully been applied to study the mechanical folding pathways of proteins and of RNA[13, 14] By using these techniques that employ simplified interaction potentials and reduced numbers of particles the details of the formation and rupture of noncovalent bonds cannot be studied with atomistic resolution. The CG forces acting on the virtual sites are distributed uniformly among the neighboring atoms to achieve the coupling between the different parts of the system We have applied this methodology to the special non-equilibrium situation encountered in FPMD simulations and we have found that the scheme is applicable in principle but the accuracy is not comparable to the one in equilibrium situations[22]. We compare the results of FPMD simulations performed employing AdResS to those of AA simulations and close with some concluding remarks
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