Kavraki Lab

Introduction

Multiscale techniques have recently emerged as promising tools to combine the efficiency of coarse-grain simulations with the detail of all-atom simulations for the characterization of a broad range of molecular systems in fields such as material science and biophysics. The underlying assumption in the definition of multiscale techniques for protein simulation is that it is possible to reliably and efficiently move between coarse-grain and all-atom models. In this work we have taken steps towards showing that this assumption holds and provide a method for moving between coarse-grain and all-atom simulations efficiently. By demonstrating that it is feasible to reliably and quickly move between a coarse-grain model and an all-atom model, this work should open doors for future work on multiscale simulations.

Methods

The Reconstruction Algorithm for COarse-Grain Structures (RACOGS) was designed for the purpose of multiscale modeling of protein landscapes. For the reconstruction method to be useful there must be a high probability that the coarse-grain structure will produce a reasonable all-atom structure. During multiscale modeling any valid coarse-grain structure may be considered a candidate for reconstruction. At the same time, the method must also be efficient enough to reconstruct hundreds of thousands of coarse-grain structures in a reasonable amount of time. This is a key difference from previous reconstruction methods: While existing methods focus on the recovery of a native-like geometry, RACOGS was designed specifically to obtain physically realistic all-atom structures in any region of the folding landscape visited by coarse-grain protein simulations.

Application: SH3 and S6

All-atom reconstruction was performed on 606,000 coarse-grain structures for each of src-SH3, wildtype S6 (S6wt) and a mutant variant of S6 (S6Alz) which misfolds. The coarse-grain structures were obtained from simulations using a minimalist protein model at the folding temperature of the proteins. A comparison of the all-atom free energy landscape with the free energy landscapes calculated using the coarse-grain structures showed no apparent distortion. Additionally, further examination of the all-atom structures obtained in the misfolded region of S6Alz and in the transition state ensemble src-SH3 showed good agreement with previous experimental and computational evidence.

The free energy landscape of src-SH3 at the folding temperature, obtained using (a) coarse-grain (b) all-atom structures reconstructed with RACOGS. The free energy is calculated as a function of the fraction of native contacts, Q, and the fraction of non-native contacts, A. Each contour level marks a free energy change of 1 RTf.

The free energy surface of S6wt at the folding temperature, calculated using (a) coarse-grain (b) all-atom structures reconstructed with RACOGS. The free energy is shown as a function of the fraction of native contacts, Q, and the fraction of non-native contacts, A. Each contour level marks a free energy change of 1 RTf.

The free energy landscape of S6Alz calculated using (a) coarse-grain or (b) all- atom structures, at the folding temperature. The free energy is plotted as a function of the fraction of native contacts, Q, and the fraction of non-native contacts, A.