The most successful protocols for building protein structure models have been template-based methods. These involve selecting whole or parts of known protein structures and assembling them to form an initial model of the target sequence of interest. This initial model can then be altered or refined to (hopefully) achieve higher accuracy. One method to make these adjustments is to use molecular dynamics simulations to sample different conformations of the structure. A “refined” model can then be taken as a low-energy state that the simulation converges to. However, whilst physics-based potentials are effective for certain aspects of refinement (e.g. relieving clashes between side chain atoms), the task of actually improving overall model quality has so far proved to be too ambitious.
In this paper entitled “Atomic-Level Protein Structure Refinement Using Fragment-Guided Molecular Dynamics Conformation Sampling,” Jian et al demonstrate that current MD refinement methods have little guarantee of making any improvement to the accuracy of the model. They therefore introduce a technique of supplementing physics-based potentials with knowledge about fragments of structures that are similar to the protein of interest.
The method works by using the initial model to search for similar structures within the PDB. These are found using two regimes. The first is to search for global templates by assessing the TMscore of structures to the whole initial model. The second is to search for fragments of structures by dividing the initial model into continuous 3 secondary structure elements. From these sets of templates and the initial model, the authors can generate a bespoke potential for the model based on the distances between Cα atoms. By doing this, additional information about the likely global topology of the protein can be incorporated into a molecular dynamics simulation. The authors claim that this enables the MD energy landscape is therefore reshaped from being “golf-course-like” being “funnel-like”. Essentially, the MD simulations are guided to sample conformations which are likely (as informed by the fragments) to be close to the target protein structure.
Does it work?
As a full solution to the problem of protein structure model refinement, the results are far from convincing. Quality measures show improvement in only the second or third decimal place from the initial model to the refined model. Also, as might be expected, the degree to which the model quality is improved is dependent on the accuracy of the initial of the model.
However, what is important about this paper is that, although small, the improvements made do exist in a systematic fashion. Previously, attempts to refine a model using MD not only failed to improve its accuracy but would be likely to reduce its quality. Fragment-guided MD (FG-MD) and the explicit inclusion of a hydrogen bonding potential, is not only able to improve the conformations of side chains but also improve (or at least not destroy) the global backbone topology of a model.
This paper therefore lays the groundwork for the development of further refinement methods that incorporate the knowledge from protein structure fragments with atomically detailed energy functions. Given that the success of the method is related to the accuracy of the initial model, there may be scope for developing similar techniques to refine models of specific proteins where modelling quality is already good. e.g. antibodies.