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The future of protein modeling: integrative modeling

In this paper, Russel et al. set up the grounds for the next generation of protein modeling platforms that combine computational modeling with experimental information from various sources. This will permit us to re-assess and refine published structural models as new structural information becomes available and suggest future experiments that validate the refined model in a feed-back loop.

In the integrative modeling platform, models are encoded as a collection of particles. Each particle can be used to create atomic, coarse-grained, or hierarchical representations. Models are then evaluated by a scoring function composed of terms called restraints. Each restraint corresponds to one particular experiment and measures how well a model agrees with the structural information derived from that experiment. The IMP’s scoring function includes restraints for small-angle X-ray scattering (SAXS), mass spectrometry, electron microscopy, nuclear magnetic resonance (NMR), Chemistry at Harvard Macromolecular Mechanics (CHARMM) force field, statistical potentials, alignment with related structures and 5C data. 

IMP also integrates different sampling algorithms that will allow users to refine each model so that it fulfils the restraints dictated by the different experimental information. Furthermore, IMP has been implemented so that external users can also develop new restraints, optimization algorithms and analysis methods.

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A beautiful friendship: Combining X-ray crystallography and cryo-electron microscopy

Trabuco and colleagues introduce a very interesting approach that combines high-resolution data from X-ray crystallography with lower-resolution electron density maps obtained by cryo-electron microscopy (cryo-EM). This method, known as MDFF (molecular dynamics flexible fitting) incorporates two new variables into its MD potential energy function, one that corresponds to a potential derived from the EM data and another variable that aims to preserve the secondary structure of proteins and nucleic acids.

Such combination permits to take the knowledge that you can extract from cryo-EM maps further. It is important to highlight that the EM map represents an ensemble of conformational states even when dealing with a homogeneus dataset. Therefore, it is preferred to show how not just a single fitted structure but a set of differently structures fitted equally well into a single cryo-EM map. Something similar to the ensemble of structures obtained by NMR.

To our knowledge, this is the only method for flexible fitting capable of dealing with nucleic acids and proteins. The authors release newer versions from time to time (they recently incorporated symmetry restraint into the simulation. I would recommend this method to anyone who is planning to apply a flexible fitting method in his/her research.

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Modular evolution and the origins of symmetry

Broom and colleagues study the molecular evolution of protein domains and the origins of the symmetry of a particular protein domain, known as beta-trefoil.A new protein domain is engineered computationally and subsequently characterized structurally.

This paper provides new insights into the evolution of the symmetry of protein domains and into protein engineering. The authors show that the widely adopted domain duplication and divergence model is not the only source for domain evolution. A new evolutionary model is described, according to which a particular subdomain can lead to the assembly of a new symmetry-based protein domain by combining several repeats of the same subdomain. The latter implies that modular evolution is an ongoing process.

The authors computationally designed a new beta-trefoil subdomain and repeated it into a single chain to form a new three-fold globular protein. The model was then expressed, purified, and structurally characterized. The newly designed protein was found to be highly soluble, stable, and functional. Furthermore, while the single subdomain cannot fold by itself, the single chain containing the three copies of the subdomain folds into a single and stable domain. This indicates a significant energy penalty for forming the beta-trefoil fold from separate chains.  The authors also discuss the benefits of internally symmetric structures for protein function.

A new protein domain is engineered computationally and subsequently characterized structurally.  This paper provides new insights into the evolution of the symmetry of protein domains and into protein engineering. The authors show that the widely adopted domain duplication and divergence model is not the only source for domain evolution. A new evolutionary model is described, according to which a particular subdomain can lead to the assembly of a new symmetry-based protein domain by combining several repeats of the same subdomain. The latter implies that modular evolution is an ongoing process.  The authors computationally designed a new beta-trefoil subdomain and repeated it into a single chain to form a new three-fold globular protein. The model was then expressed, purified, and structurally characterized. The newly designed protein was found to be highly soluble, stable, and functional. Furthermore, while the single subdomain cannot fold by itself, the single chain containing the three copies of the subdomain folds into a single and stable domain. This indicates a significant energy penalty for forming the beta-trefoil fold from separate chains.  The authors also discuss the benefits of internally symmetric structures for protein function.