Quantum mechanics and free energy calculations in drug design and catalysis
Title: Quantum mechanics and free energy calculations in drug design and catalysis
SNIC Project: SNIC 2021/5-137
Project Type: SNIC Medium Compute
Principal Investigator: Katarina Roos <katarina.roos@icm.uu.se>
Affiliation: Uppsala universitet
Duration: 2021-04-01 – 2022-04-01
Classification: 10407 30103 10602
Homepage: http://www.icm.uu.se/bbbi/


An important role of computer aided drug design is to guide modifications of ligands to improve binding to the protein target. Free energy (FE) methods are some of the most rigorous to calculate protein-ligand free energy of binding. Although FE methods have been shown to predict the relative affinity for a wide range of systems, there are cases where polarization effects are important and the current fixed charge classical force fields are inadequate. With a high level quantum mechanical (QM) method these effects can be described, however, extensive conformational sampling is at present computationally too expensive. The main objective of my research is to use and combine QM and free energy FE methods to model fundamental interactions between molecules in challenging and biochemically interesting targets, where both polarization and dynamical effects are important. The goals of the proposed research are to develop methods to describe interactions between organic molecules and metals, to address two problems; one, how proteins bind and use metal ions in their active site for function, and two, how small drugs bind to the metal ions in the proteins to block activity. We anticipate that our successful work will result in increased understanding of how important biological metalloproteins work, how they can be tuned to do different activities with different metals, and enable design of novel drugs that can inhibit their activity when they lead to disease. Some initial studies: Ribonucleotide reductase (RNR) is an essential protein responsible for generating the building blocks for DNA in every living organism. The oxygen dependent class I RNR use a dimetal cofactor to generate the radical (di-iron, di-manganese or mixed iron-manganese). Recently a new metal free subclass Ie was discovered that instead use a dopa radical as cofactor (Högbom, Nature 2019). QM and FE calculations will be employed to characterize the protein radical states involved, and deduce the mechanism for radical initiation, and to relate that to the metal dependent subclasses. The work is conducted in collaboration with Prof. Högbom at Stockholm University. Prediction of protein-ligand binding affinities with QM and FE methods will initially be focused on systems with complicated electronic effects, including a set of zwitterionic compounds with various acid analogues and pKa effects binding to a drug target, and fragments binding to metal sites in metallotargets to identify novel metal binding groups.