Web-based computational chemistry education with CHARMMing II: Coarse-grained protein folding.

Frank C Pickard,Benjamin T Miller,H Lee Woodcock,Bernard R Brooks,Vinushka Schalk,Michael G Lerner

doi:10.1371/journal.pcbi.1003738

Abstract

A lesson utilizing a coarse-grained (CG) G-like model has been implemented into the CHARMM INterface and Graphics (CHARMMing) web portal (www.charmming.org) to the Chemistry at HARvard Macromolecular Mechanics (CHARMM) molecular simulation package. While widely used to model various biophysical processes, such as protein folding and aggregation, CG models can also serve as an educational tool because they can provide qualitative descriptions of complex biophysical phenomena for a relatively cheap computational cost. As a proof of concept, this lesson demonstrates the construction of a CG model of a small globular protein, its simulation via Langevin dynamics, and the analysis of the resulting data. This lesson makes connections between modern molecular simulation techniques and topics commonly presented in an advanced undergraduate lecture on physical chemistry. It culminates in a straightforward analysis of a short dynamics trajectory of a small fast folding globular protein; we briefly describe the thermodynamic properties that can be calculated from this analysis. The assumptions inherent in the model and the data analysis are laid out in a clear, concise manner, and the techniques used are consistent with those employed by specialists in the field of CG modeling. One of the major tasks in building the G-like model is determining the relative strength of the nonbonded interactions between coarse-grained sites. New functionality has been added to CHARMMing to facilitate this process. The implementation of these features into CHARMMing helps automate many of the tedious aspects of constructing a CG G model. The CG model builder and its accompanying lesson should be a valuable tool to chemistry students, teachers, and modelers in the field.

Highlights

To function properly, most proteins must fold [1]
CG models are very attractive in an educational environment, as they retain the qualitative features of their AA counterparts and can be performed cheaply and rapidly, leading to a far more interactive experience with the students
We will use a Go-like model in which each amino acid is mapped into two CG sites, one located at the alpha carbon (Ca) and one located at the side-chain center of mass (SC)

Summary

Introduction

Most proteins must fold [1]. Determining the structure and understanding the mechanisms responsible for folding are active areas of biophysical research, as gleaning this information may provide critical insights towards fighting diseases that have been linked to protein structure, such as Alzheimer’s [2,3]. It is possible to construct a coarse-grained (CG) model, in which multiple atoms are represented by a single center (as in the right-hand panel of Figure 1) These types of models can be useful theoretical tools because they can be designed for a system or process of interest. CG models are very attractive in an educational environment, as they retain the qualitative features of their AA counterparts and can be performed cheaply and rapidly, leading to a far more interactive experience with the students In this lesson, we will use a Go-like model in which each amino acid is mapped into two CG sites, one located at the alpha carbon (Ca) and one located at the side-chain center of mass (SC). We discuss the utility of this lesson both as an educational tool and as a research aid

Methods

Discussion and Conclusion