Translational mobilities of proteins in nanochannels: A coarse-grained molecular dynamics study

Abstract

We investigated the translation of a protein through model nanopores using coarse-grained (CG) nonequilibrium molecular dynamics (NEMD) simulations and compared the mobilities with those obtained from previous coarse-grained equilibrium molecular dynamics model. We considered the effects of nanopore confinement and external force on the translation of streptavidin through nanopores of dimensions representative of experiments. As the nanopore radius approaches the protein hydrodynamic radius, r_{h}/r_{p}→1 (where r_{h} is the hydrodynamic radius of protein and r_{p} is the pore radius), the translation times are observed to increase by two orders of magnitude. The translation times are found to be in good agreement with the one-dimensional biased diffusion model. The results presented in this paper provide useful insights on nanopore designs intended to control the motion of biomolecules.

Beyond mass spectrometry, the next step in proteomics

“…According to Muthukumar (152), the mobility of a protein in a pore is affected by the excluded volume, the dynamics of the counterions and water there, as well as the interactions with the pore surface. When the pore diameter approaches the hydrodynamic diameter of the protein, the mobility collapses, and the blockade duration increases (1000-to 10,000-fold) (153), until, eventually, the molecule fails to permeate through the membrane at all. Thus, a pore of the same size as a protein can be advantageous by increasing the blockade signal measured in the pore volume and slowing the translocation velocity.…”

Mapping shifts in nanopore signal to changes in protein and protein-DNA conformation

“…When the majority of translocations cannot be detected by low-bandwidth equipment, only the longest events contribute to dwell time distributions, distorting calculated values of the protein velocity and diffusion coefficient. (53)) Haridasan et al (54) recently simulated this reduced in-pore diffusion constant, witnessing a two-ordersof-magnitude decrease from the bulk value as streptavidin translocated through an 8 nm pore under the equivalent of roughly 500 mV applied voltage. Following the results of that molecular dynamics study, the 0.73 ratio of the MSA hydrodynamic diameter (6.2 nm, see Supplemental Information S5 for calculation) to the pore diameter (8.4 nm) may cause the protein translation time to deviate from the frictional drag relationship ~ℎ/( − ℎ ) observed in larger pores.…”

“…(55) Instead, non-bonding interactions between MSA and the nanopore interior will produce excessive drag, reducing the streptavidin's mobility to a value that depends on the applied force. (54) Protein mobility in nanopore translocation experiments is routinely described (36,41,52) with the Einstein-Smoluchosky equation:…”

“…The significant reduction in the values for in-pore diffusion coefficient and corresponding mobility from the bulk values is in line with prior studies. (39,51,52,54) Interestingly, Muthukumar(51) has offered an adaption of Equation 5 which takes into account nanopore-related discrepancies such as the counterion cloud, confinement effects and protein-pore interaction. This generalization can be described as follows:…”

Langevin dynamics simulation of protein dynamics in nanopores at microsecond timescales

“…Most likely the drastic change in protein dynamics is originating from electroosmotic interactions. In order to account for hydrodynamics in such systems, generally explicit solvent molecules are considered atomistically [20][21][22] or CG 24,29 , or less often through hybrid model: coupling MD of the biomolecule with hydrodynamic interactions from Lattice-Boltzmann (LB) calculations 32 . Such hybrid model can still be computationally expensive, requiring numerical LB calculations over the grids at different timesteps.…”