The goals of this project are to:
- study the changes in structure and function that occur to protein complexes,
antibodies and pharmaceuticals due to changes in hydration, salt and pH levels;
- optimize the functionality of a class of novel protein based biosensors including the effect of the changes above; and,
- build and develop further R&D interactions with industry regarding 1. and 2. including Kerry Group , APC and other partners.
Structural changes occur to foods ingredients, bio-actives and pharmaceuticals including antibodies on drying and other methods of processing/purification. Controlling such changes are important to avoid structural damage and to maximize functionality.
The computer based simulation tools we develop to understand the nano-scale mechanisms include a novel particle insertion method (allowing for instance the hydration levels to be changed), combined with a variety of rare-event based methods, and molecular dynamics engines such as LAMMPS and - GROMACS which are capable of simulating large systems consisting of millions of atoms on massively parallel computing platforms.
We are using such tools to optimize a protein based patent pending Biosensor developed with applications in Medical Diagnostics, Scientific Visualization and Therapeutics. At the heart of the sensor is a novel protein based molecular switch which allows extremely sensitive real time measurement of molecular targets to be made, and to turn on or off protein functions and other processes accordingly. Protein functions and processes of interest include fluorescence, resonance energy transfer, enzymatic activity and toxicity. Depending on the application, the sensor needs to be functional in a variety of environments, ranging from organelles in living cells to bodily fluids such a blood serum and water. Optimizing or tuning the sensor design to suit different solvent environments and targets can be greatly facilitated using E-CAM simulation modules, as well as other community software. While coarse grained simulations are possible in some contexts, detailed simulations at a molecular level require HPC resources, and state of the art software. Optimized protein sequences are then expressed using bio-technology and molecular biology laboratory based methods, and tested.
List of Tasks
- Complete, test and fully optimize our particle insertion method in a variety of contexts (i.e. changes in salt, hydration, pH, and guest molecules).
- Develop a systematic approach to optimize molecular biosensors
- Perform a detailed commercial feasibility study for the sensor, identifying target markets and industry partners, and a commercialization strategy leading to a Start-Up.
List of Modules
- PIcore - Core module for the calculation of free energies due to particle insertion - expected delivery date Q4 2017
- PIhydrate - hydration extension of PIcore - expected delivery date Q1 2018
- PIsolvation single - Calculation of the chemical potential of a molecule inserted into single solvent species – extension of PIcore - expected delivery date Q1 2018
- PIsolvation multiple - Calculation of the chemical potential of a molecule inserted into a mixture extension of PIcore - expected delivery date Q2 2018
- Sensor - First module for rational design of molecular biosensors - expected delivery date Q3 2018
- PIpH- Calculation of proton transfer combining PIcore and quantum classical surface hopping schemes - expected delivery date Q4 2018
List of publications
- Inventor, D. MacKernan, International Patent Application PCT/IB2017/055432, September 2017 (Applicant University College Dublin)
- FL Barroso da Silva, D MacKernan, Benchmarking a fast proton titration scheme in implicit solvent for biomolecular simulations, J. Chem. Theory Comp. (2017)