Protein design aims to rationally design proteins that fold into particular target structures capable of performing new desired functions. Such an approach will undoubtedly have a huge impact in medicine and biotechnology in the future. However, and despite important recent advances in the field, efforts have had limited success in designing proteins with high affinity and selectivity for small ligands.
Baker and colleagues describe a novel computational method to design ligand-binding proteins, which is combined with directed-evolution experiments. The described computational protocol mimics properties of naturally occurring binding sites: specific hydrogen-bonding and van der Waals interactions with the ligand, shape complementarity and structural organization in the unbound state.
As a result, the designed protein is able to bind the target ligand with picomolar affinity. X-ray crystallography confirms the computer-designed ligand-binding mode. Specificity assays show that related ligands bind less tightly to the designed protein. Furthermore, fine tuning the hydrogen-bonding interactions at the designed binding site permits control of affinities over related ligands.Computational design of ligand-binding proteins is likely to have a strong influence on future protein design attempts and, as the authors state, “should provide an increasingly powerful approach to creating small molecule receptors for synthetic biology, therapeutic scavengers for toxic compounds, and robust binding domains for diagnostic devices”.
This paper describes a major breakthrough in the structural biology of the mature HIV-1 virus, and it is a good example on how computational modeling can expand the knowledge provided by experimental methods.
This work combines cryo-electron microscopy (cryo-EM) of HIV-1 tubular assembly and cryo-electron tomography of HIV-1 cores isolated from virions, along with previously published crystal structures of the HIV-1 capsid protein. For this, molecular modeling and all-atom molecular dynamics flexible fitting are applied, and, as a result, a complete capsid model is shown at pseudo-atomic resolution.The obtained results highlight a three-helix bundle in the carboxy term of the capsid protein, which is essential for viral assembly, stability and infectivity. Thus, this work suggests a direction for future pharmacological studies.
Studies of molecular evolution at the protein structure level permit the identification of fundamental mechanisms that shape protein function in its broadest definition (catalyzed chemical reaction, interacting partners, and cellular localization). To be functional, most proteins assemble into macromolecular complexes following an ordered sequence of events.
In this paper, Marsh and colleagues describe, for the first time, the intimate relationship between pathways of protein assembly, quaternary structure, and gene fusion in heteromeric complexes. This research shows a new perspective on gene fusion that will permit a better interpretation of fusion-based predictions. Moreover, the authors provide fundamental evidence to be considered in any future attempt of protein engineering based on gene fusion strategies.