Computational protein structure refinement: almost there, yet still so far to go

Abstract

Protein structures are essential in modern biology yet experimental methods are far from being able to catch up with the rapid increase in available genomic data. Computational protein structure prediction methods aim to fill the gap while the role of protein structure refinement is to take approximate initial template-based models and bring them closer to the true native structure. Current methods for computational structure refinement rely on molecular dynamics simulations, related sampling methods, or iterative structure optimization protocols. The best methods are able to achieve moderate degrees of refinement but consistent refinement that can reach near-experimental accuracy remains elusive. Key issues revolve around the accuracy of the energy function, the inability to reliably rank multiple models, and the use of restraints that keep sampling close to the native state but also limit the degree of possible refinement. A different aspect is the question of what exactly the target of high-resolution refinement should be as experimental structures are affected by experimental conditions and different biological questions require varying levels of accuracy. While improvement of the global protein structure is a difficult problem, high-resolution refinement methods that improves local structural quality such as favorable stereochemistry and the avoidance of atomic clashes are much more successful.

Discrimination of Native-like States of Membrane Proteins with Implicit Membrane-based Scoring Functions

“…Future efforts may focus on this aspect as well, although it is not clear that exactly targeting a crystal structure obtained under non-biological conditions would result in the most useful predictions. 30 …”

“…Protein structure scoring functions are also important for computational protein design 28–29 and during protein structure refinement of template-based models. 30–32 …”

Driven to near‐experimental accuracy by refinement via molecular dynamics simulations

“…Despite many successes with protein structure prediction, the resulting models often retain inaccuracies and fail to reach the accuracy of true experimental structures. Consequently, there have been increased efforts on improving predicted models via refinement as a final touch . In the early 2010s, a few successful protein model refinement protocols began to emerge .…”

What makes it difficult to refine protein models further via molecular dynamics simulations?

“…Complementary to the advances outlined above, protein structure refinement methods have been increasingly successful in further improving initial knowledge‐based predictions via ab initio techniques . Evidence of significant protein structure refinement has first emerged around 2010, at CASP9 .…”