Modulating Mobility: a Paradigm for Protein Engineering?

Abstract

Additional Information:Question ResponsePlease select a section/category for your manuscript.Biocatalysis for organic synthesis -Novel and significant advances in biocatalysis for organic synthesis, including chemo-, regio-and enantioselective biotransformation, screening and engineering of novel enzymes for biocatalysis, biocatalyst immobilization, and nonaqueous biocatalysis.Abstract: Proteins are highly mobile structures. In addition to gross conformational changes occurring on, for example, ligand binding, they are also subject to constant thermal motion. The mobility of the protein varies through its structure and can be modulated by ligand binding and other events. It is becoming increasingly clear that this mobility plays an important role in key functions of proteins including catalysis, allostery, cooperativity and regulation. Thus, in addition to an optimum structure, proteins most likely also require an optimal dynamic state. Alteration of this dynamic state through protein engineering will affect protein function. A dramatic example of this is seen in some inherited metabolic diseases where alternation of residues distant from the active site affects the mobility of the protein and impairs function. We postulate that using molecular dynamics simulations, experimental data or a combination of the two it should be possible to engineer the mobility of active sites. This may be useful in, for example, increasing the promiscuity of enzymes. Thus, a paradigm for protein engineering is suggested in which the mobility of the active site is rationally modified. This might be combined with more "traditional" approaches such as altering functional groups in the active site. Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation Manuscript #ABAB-D-16-00805 Modulating mobility: a paradigm for protein engineering? Margaret McAuley and David J. TimsonReviewer: Flexibility of protein plays an important role in protein functions such as activity and stability. Up to now, a number of studies strategized for engineering the protein towards desirable properties are published. The manuscript has a great summary of recent studies based on modulating mobility of protein especially in activity aspect. I recommend its publication after addressing the following issue.Response: We thank the reviewer for his/her support and encouraging remarks.There are also many reports about the improvement of stability of protein by modulating the flexibility of protein. Such as, "Park.H.J et al, Computational approach for designing thermostable Candidaantarctica lipase B by molecular dynamics simulation; Zhu, F., et al, Rational substitution of surface acidic residues for enhancing the thermostability of thermolysin; Chen, J et al, Improving stability of nitrile hydratase by bridging the salt-bridges in specific thermal-sensitive regions, and so on". It would be attractive if the authors could incorporate some examples that explain the relationship between activity and stability modulated by flexibility of prote...

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