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

Abstract

A lesson utilizing a coarse-grained (CG) Gō-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 Gō-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 Gō model. The CG model builder and its accompanying lesson should be a valuable tool to chemistry students, teachers, and modelers in the field.

Figure 1. The native structure of the GA module of an albumin binding domain.

Three representations of the structure are shown. The left panel shows the backbone of the native fold as a ribbon, which highlights the helical nature of the secondary structure. The center panel shows the AA structure, which is used to build the KT G model (right panel).

Figure 2. An example trajectory.

The fraction of native contacts are plotted as a function of time. By inspecting the histogram at the right, we observe that this trajectory was simulated below , as the protein is folded for 62% of the simulation.

Figure 3. An example melting curve.

Each point on the plot represents calculated from a full trajectory. occurs when , and the curvature of the plot is related to .

Figure 4. The workflow of the KT G model lesson.

Blue boxes represent the steps described in the text. Yellow boxes show the inputs and outputs of each step. Note that the CHARMM protein structure file is only built when a calculation is performed (minimization, in this case). Q is the fraction of native contacts as defined in the text.