Computational Protein Design of Hybrid Nanopores for Biomolecular Sensing

Cutting-edge DNA sequencing technology utilizes biological nanopores, which boast nanoscale sensing volumes that enable the discrimination of individual bases within a single DNA molecule. However, a relatively low number of pores can feasibly be integrated on a single sensor chip, typically numbering in the hundreds to low thousands. This constraint significantly hampers the technology's throughput, measured in terms of molecules analyzed per unit of time.

In contrast, solid-state nanopore technology is significantly more scalable compared to its biological counterpart. With CMOS process technology, we are now able to manufacture nano-scale devices, such as Field-Effect Transistors (FETs), with feature sizes down to 7 nm. Billions of nanoscopic FETs can now be seamlessly integrated on a chip. The continuous advancement of CMOS technology not only keeps revolutionizing computing capabilities but also unlocks new frontiers in various domains, such as bio-sensing for proteomics, transcriptomics and genomics.

The advantageous scalability and robustness of solid-state nanopore technology can be leveraged for the next generation of biosensors. However, several challenges must be addressed to fully unlock its potential. These challenges encompass issues such as sensitivity limitations and the variability in sensitivity across solid-state nanopores. A promising avenue involves the fusion of a biological nanopore with a solid-state nanopore, creating a hybrid nanopore. The primary goal of this hybrid approach is to impart the high sensitivity of biological nanopores to their solid-state counterparts. Nevertheless, the current concepts for hybrid nanopores encounter hurdles at the interface of biological and solid-state pores, leading to leakage and imperfect fits.

In this PhD computational protein design will be leveraged to develop versatile hybrid nanopores to tackle the present challenges. The candidate will leverage state-of-the-art computational modelling tools to design novel proteins, based on the family of transmembrane beta-barrel (TMB) proteins. TMBs typically form stable and rigid pores through a lipid bilayer and are hence excellent potential scaffolds for the engineering of nanopore sensors and transmembrane channels. To find the best possible fit to solid-state pores, we will use de novo protein design, biophysics and structural biology experiments, combined with cutting-edge semiconductor processing techniques and surface coating technologies such as organic self-assembled monolayers or inorganic atomic layer deposition.

As this topic requires in-depth understanding of both experiment and theory, this Ph.D. candidate will perform diverse, hands-on labwork (bio-chemistry, cleanroom, and electrical characterization labs) in addition to state-of-the-art molecular modeling and device simulation research.

Imec is soliciting enthusiastic PhD candidates to advance single-molecule electrical sensing technology, approaching the problem both from the experimental and modeling side.