Protein synthesis release factors (RF1 and RF2) as targets for new antibiotics
Title: Protein synthesis release factors (RF1 and RF2) as targets for new antibiotics
SNIC Project: SNIC 2014/1-241
Project Type: SNAC Medium
Principal Investigator: Johan Åqvist <aqvist@xray.bmc.uu.se>
Affiliation: Uppsala University
Duration: 2014-08-01 – 2015-08-01
Classification: 10601
Keywords:

Abstract

Antibiotics are natural substances that stop bacterial growth. Due to the widespread use of antibiotics since the 1940s, the bacteria constantly become increasingly resistant to these drugs, and over the last years, resistant bacteria have become very common, leading to increased disease, mortality, and costs to society. A key strategy is to disrupt the processes that lead directly to the generation of new proteins, thereby stopping or slowing bacterial growth. Protein synthesis is performed by a complex organelle, the ribosome, and further approx. 100 proteins and RNA molecules. The purpose of this project is twofold: First, we will search for putative binding sites that can bind new compounds inhibiting the protein synthesis. We will try to find molecules that specifically bind to so-called termination factors, leading to bacterial growth defects. Both X-ray crystallography and NMR experiments have demonstrated that organic solvents bind precisely at druggable sites and this effect has been showed to be reproduced using molecular dynamics with a binary solvent. Thus, in the first part we will perform several molecular dynamics simulations replicas of the release factor systems in mixed solvents and analyze the interaction free energies between the protein and small organic molecules. The next step is to select putative drugs from a screening library and analyze the protein-ligand interaction applying free energy perturbation methods. The aim of the second part of the project is to increase our fundamental knowledge of the ribosome and protein synthesis in terms of structure and function. This basic knowledge is a necessary condition for effectively being able to identify new antibiotics candidates and substances that can prevent bacterial growth. We thus also expect to run multiple dimension replica exchange molecular dynamics simulations to elucidate the mechanism by which eukaryotic release factors bind to the stop codons. The project is carried out in close collaboration with experimental groups and predictions from our computer simulations will eventually be tested by both in vitro and in vivo experiments.