Abstract
Globular proteins are held together by interacting networks of amino acid residues. A number of different structural and computational methods have been developed to interrogate these amino acid networks. In this review, we describe some of these methods, including analyses of X-ray crystallographic data and structures, computer simulations, NMR data, and covariation among protein sequences, and indicate the critical insights that such methods provide into protein function. This information can be leveraged towards the design of new allosteric drugs, and the engineering of new protein function and protein regulation strategies.
Highlights
It has long been understood that interactions at the local level (e.g. Hbonding, steric interactions) dictate the formation of protein structural elements, such as α-helices and β-sheets, and that local interactions dictate the packing of these various structural elements to form threedimensional protein structure
With these energetic considerations in mind, globular proteins can be viewed as being held together by a series of local interactions through networks of interacting amino acid residues. These amino acid networks (Fig. 1) have been termed ‘residue interaction networks’ [4], ‘protein structure networks’ [5], ‘contact networks’ [6], ‘pathways’ [7], ‘circuits’ [8], ‘wiring diagrams’ [9], ‘protein sectors’ [10] and so on. Intrinsic to this viewpoint is the idea that some interactions and amino acid residues are more important than others, such that the amino acid network generally represents a subset of all potential interactions and residues within a protein
This method was used to generate networks for cyclophilin A [59] and E. coli dihydrofolate reductase (DHFR) [58]; amino acid substitutions at CONTACT-determined network positions led to dramatic decreases in enzyme activity in both of these systems
Summary
It has long been understood that interactions at the local level (e.g. Hbonding, steric interactions) dictate the formation of protein structural elements, such as α-helices and β-sheets, and that local interactions dictate the packing of these various structural elements to form threedimensional protein structure (e.g. ref. [1,2]). With these energetic considerations in mind, globular proteins can be viewed as being held together by a series of local interactions through networks of interacting amino acid residues. These amino acid networks (Fig. 1) have been termed ‘residue interaction networks’ [4], ‘protein structure networks’ [5], ‘contact networks’ [6], ‘pathways’ [7], ‘circuits’ [8], ‘wiring diagrams’ [9], ‘protein sectors’ [10] and so on. ⁎ Corresponding author at: 107 Chemistry Building, The Pennsylvania State University, University Park, PA, USA
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