Monte Carlo approach to proteins in cellular environments
The interior of living cells is a crowded environment where high concentrations of macromolecules are present. However, biophysical studies of proteins are often conducted in dilute solutions. A fundamental and long-standing question, therefore, is how macromolecular crowding affects reactions such as proteins folding, binding and aggregation. This question is currently being intensely studied by both experimental and computational methods. The aim of this project is to develop and apply novel computational methods for the study of proteins in crowded environments. Our approach builds on the existing Monte Carlo-based program PROFASI , which was developed by us through folding thermodynamics studies of a structurally diverse set of peptides and small proteins. Recently, this code was re-optimized for large systems, and then used to simulate, for the first time, folding-unfolding equilibria of peptides in the presence of protein crowders [2-4]. This project will focus on the following two specific goals: (i) A combined Monte Carlo and NMR investigation of the unfolding of the SOD1 protein, whose misfolding has been implicated in the ALS disease, in the presence protein crowders. This is a collaboration with Prof. Mikael Akke, Biophysical Chemistry, Lund. This work started more than a year ago and a first set of both simulations and NMR experiments has been completed. (ii) Development of methods based on Markov modeling techniques for interpretation and analysis of simulations of crowded systems. Here, the aim is to create a systematic procedure for identification of relevant states and reaction pathways in these complex systems. The methods are tested through simulations of model systems consisting of one test peptide and around ten crowder proteins. References: 1. A. Irbäck and S. Mohanty. PROFASI: A Monte Carlo simulation package for protein folding and aggregation. J. Comput. Chem. 27, 1548 (2006). 2. A. Bille, B. Linse, S. Mohanty and A. Irbäck. Equilibrium simulation of trp-cage in the presence of protein crowders. J. Chem. Pays. 143, 175102 (2015). 3. A. Bille, S. Mohanty and A. Irbäck. Peptide folding in the presence of interacting protein crowders. J. Chem. Phys. 144, 175105 (2016). 4. A. Irbäck and S. Mohanty. Protein folding/unfolding in the presence of interacting protein crowders. Eur. Phys. J. - Spec. Top. 226, 627-638 (2017).