In our research, we used a one-bead-per-amino acid coarse-grained molecular dynamics model of the disordered phase of the nuclear pore complex (NPC) to investigate the transport of particles of varying surface properties such as size, hydrophobicity, and charge.
The image featured on the cover of the January 21 issue of Biophysical Journal is Figure 1d from our article “Charge of karyopherins and nuclear FG-Nups are key ingredients of nucleocytoplasmic transport.” It was designed to visually capture the dynamics of the NPC, including details of the experimentally calibrated molecular dynamics model. This model is used to simulate interactions between transport particles (large blue spheres composed of overlapping charged beads and small red hydrophobic beads) and the intrinsically disordered proteins inside the NPC called “FG-nucleoporins” (FG-Nups). The FG-Nups are represented by chains of colored beads, where each bead represents one specific amino acid residue. The nature and sequence of the amino acids dictate the binding affinities between the FG-Nups and the transporting particles, collectively determining the transport rates. To compose this image, we used the visual molecular dynamics tool.
This image summarizes the modeling approach that we use to uncover the biophysical principles underlying nucleocytoplasmic transport. The NPC acts as a selective gateway, facilitating the exchange of molecules between the nucleus and cytoplasm while maintaining compartmental integrity. Our work reveals that small neutral particles can translocate through the NPC, whereas the transport rates drastically slow down for larger particles. However, when these larger transport particles are made negatively charged, the particles can readily translocate through the NPC, and the addition of hydrophobic binding sites further enhances the transport rates. Interestingly, the transport rate peaks at a charge and hydrophobicity similar to those of Kap95 (a native transport receptor from the karyopherin family). The image symbolizes the dynamic and random nature of these molecular exchanges, showcasing that the charge-dependent binding and unbinding dynamics are critical for NPC function. As such, the image is a nice scientific summary of our research, in which we build computational techniques that can serve as a conceptual lens into the microscopic biological processes that sustain cellular life.
Our research has broad implications for understanding cellular logistics and human health. For instance, in regard to drug-delivery systems, understanding the underlying principles governing NPC selectivity and transport mechanisms is instrumental for the design of nanoparticle-based drug-delivery systems, improving their ability to penetrate nuclear barriers for targeted therapies. With respect to aging and neurodegenerative diseases, degradation of NPC components is a marker of aging and is linked to cancer and neurodegeneration. Understanding the molecular principles underlying nuclear transport can provide a framework to explore potential therapeutic interventions. For synthetic biology, the principles of nucleocytoplasmic transport can guide the engineering of synthetic cells with functional compartments, advancing applications in biotechnology and nanomedicine.
The principles revealed through our study extend to broader areas of science and technology. For example, in the area of cell biology and material science, the competition between charge and hydrophobic interactions studied here for FG-Nups are also key drivers of phase separation into biological condensates and can inspire the design of smart polymers or selective membranes. For computational modeling, our work demonstrates the power of combining computational and experimental approaches to tackle complex biological systems, providing a roadmap for similar studies in other fields.
The readers can explore our latest research, publications, and ongoing projects on our lab’s website: https://www.rug.nl/research/zernike/micromechanics/onck-group/.
—Ankur Mishra, Erik Van der Giessen, and Patrick R. Onck