Molecular Dynamics Simulations On Translocation Of Polymer And Protein Through Nanopore

Polymer molecules are made up of basic units connected by covalent bonds.The chemical properties of the polymer unit,the degree of polymerization,and the microstructure are the main factors that determine the properties of the polymer system.The nanopore technology will help us to study the internal structure of polymers.Structure determines function,so exploring the basic structure of polymers can not only deepen the understanding of structural biology,but also provide theoretical support for the development,design and application of polymers.The potential applications include improving the properties of polymers,regulating the direct interaction between polymers and other molecules,and exploring the structure and function of intrinsically disordered proteins.Molecular dynamics(MD)simulation has been widely used in biological macromolecules such as protein and DNA,and has built a bridge between the microscopic atomic level and the macroscopic matter.We use MD simulation methods to study the dynamics of a polymer or protein translocating through nanopores.Particularly,we use Langevin dynamics and coarse-grained models to study the translocation dynamics of a looped polymer chain,and use steered molecular dynamics to study the structure,force spectrum and unfolding process of an intrinsically disordered protein(here,polyQ)and calmodulin(CaM)translocating through graphene nanopores.The major works of this paper are summarized as follows:1.Using Langevin dynamics method to study the translocation process of a polymer chain with a closed loop at the center through a model nanopore.We found that when the chain length is constant,the loop translocation time τloop increases exponentially with the loop length Nloop,while the translocation time τ of the entire polymer chain decreases with the increase of Nloop.In addition,the looped polymer chain has six main pathways,each of which can produce a unique ionic current(blocking degree).The choice of pathway and the translocation dynamics in each path is highly dependent on the pore diameter of the nanopore,the ring length and the entire polymer chain length.2.Using steered molecular dynamics to explore the structural properties and force spectrum of an amorphous protein(polyQ).Since the length of polyQ is related to Huntington’s disease to a certain extent,we simulated the translocation of polyQ with different lengths(Q22,Q36,Q46)stretched through graphene nanopores of different sizes(with a diameter～1 nm and 1.5 nm).The results showed that under the same stretching constant speed,the translocation time of polyQ,the average force and work to stretch polyQ have a non-linear increase with the increase of the length of polyQ.By further analyzing the corresponding conformations of the force peaks,we found that the long chain forms more abundant secondary structures such as β-sheets,and new conformations during stretching.As the length of polyQ increases,the number of hydrogen bonds in polyQ increases too.Especially the residues in side chains would form more hydrogen bonds than main chains,which may be one of the reasons that lead to the aggregation of long-chain polyQ and cause diseases.3.Using steered molecular dynamics to stretch calmodulin(CaM)through graphene nanopores.CaM plays the role of Ca2+signal regulation in the life system.There are two representative conformations:Holo-CaM in an active state with four Ca2+ and Apo-CaM in the inactive state without Ca2+.We found that graphene nanopores with a diameter of about 1.5 nm can distinguish these two conformations to a certain extent.The Ca2+in Holo-CaM can increase the resistance of the binding area against external force stretching.When Ca2+together with its binding region passing through the nanopore,peaks can be seen in the force spectrum.And the binding region could be retained for a period of time even after passing through the nanopore.Under the same conditions of constant stretching,Apo-CaM will be stretched longer,but the average tensile force and work are smaller than those of Holo-CaM,respectively.