Abstract
A superkine variant of interleukin-2 with six site mutations away from the binding interface developed from the yeast display technique has been previously characterized as undergoing a distal structure alteration which is responsible for its super-potency and provides an elegant case study with which to get insight about how to utilize allosteric effect to achieve desirable protein functions. By examining the dynamic network and the allosteric pathways related to those mutated residues using various computational approaches, we found that nanosecond time scale all-atom molecular dynamics simulations can identify the dynamic network as efficient as an ensemble algorithm. The differentiated pathways for the six core residues form a dynamic network that outlines the area of structure alteration. The results offer potentials of using affordable computing power to predict allosteric structure of mutants in knowledge-based mutagenesis.
Highlights
Mutation of one or more residues into other amino acids through computational or experimental methods is often needed to attain a desired function in protein engineering for the purpose of either academia or industry [1]
To examine which computational program is suitable to determine the dynamic network of a protein, we first analyzed the widely studied protein cyclophilin A (CypA) in terms of cross-correlation using conventional molecular dynamics simulations
CypA was once tested as a model protein in which the collective nature of the dynamics and those residues build a common dynamic network via Nuclear Magnetic Resonance (NMR) experiments
Summary
Mutation of one or more residues into other amino acids through computational or experimental methods is often needed to attain a desired function in protein engineering for the purpose of either academia or industry [1]. Crystal structure of the derivative of substituting six core residues away from the binding sites (helices A and C) to IL-2Rβ revealed that the mutations caused such allosteric structure alteration that the mutant structure became closer to the IL-2Rβ bound state structure of IL-2 and enhanced its binding affinity for IL-2Rβ [12]. It has not been interrogated regarding how the mutated residues located in the core region away from the binding interface influence the conformation and, increase binding affinity and activity
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