Recent advances in computational protein design

Pantazes, Robert J.; Grisewood, Matthew J.; Maranas, Costas D.

doi:10.1016/j.sbi.2011.04.005

Cited by 81 publications

(66 citation statements)

References 57 publications

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“…Both tasks require the reliable re-design of enzymes either using de novo [69] or evolutionary techniques [70]. Several computational design techniques have been proposed for improving enzyme turnover number, substrate specificity, reduced allosteric inhibition, among others [71][72][73], but reliable protein design remains elusive [74]. Improvements in our ability to model and predict the outcome of biological processes and networks coupled with falling DNA synthesis costs and efficient DNA assembly tools are bringing closer to fruition the dream of the design and assembly of synthetic production hosts uniquely tailored for bio-product biosynthesis.…”

Section: Future Perspectivesmentioning

confidence: 99%

Advances in de novo strain design using integrated systems and synthetic biology tools

Khodayari

Chowdhury

et al. 2015

Current Opinion in Chemical Biology

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Recent efforts in expanding the range of biofuel and biorenewable molecules using microbial production hosts have focused on the introduction of non-native pathways in model organisms and the bio-prospecting of non-model organisms with desirable features. Current challenges lie in the assembly and coordinated expression of the (non-)native pathways and the elimination of competing pathways and undesirable regulation. Several systems and synthetic biology approaches providing contrasting top-down and bottom-up strategies, respectively, have been developed. In this review, we discuss recent advances in both in silico and experimental approaches for metabolic pathway design and engineering, with a critical assessment of their merits and remaining challenges.

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Section: Future Perspectivesmentioning

confidence: 99%

Advances in de novo strain design using integrated systems and synthetic biology tools

Khodayari

Chowdhury

et al. 2015

Current Opinion in Chemical Biology

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“…Most CPD algorithms sample an enormous number of amino acid types and side-chain conformations to find the most energy-favored sequences in the context of a single, fixed, backbone structure [1,2]. Leveraging the speed of modern computers, CPD can effectively reduce the vast sequence space to an affordable number of sequences for experimental examination.…”

Section: Introductionmentioning

confidence: 99%

Using Molecular Dynamics Simulations as an Aid in the Prediction of Domain Swapping of Computationally Designed Protein Variants

Mou

Huang

Thomas

et al. 2015

Journal of Molecular Biology

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In standard implementations of computational protein design, a positive-design approach is used to predict sequences that will be stable on a given backbone structure. Possible competing states are typically not considered, primarily because appropriate structural models are not available.One potential competing state, the domain-swapped dimer, is especially compelling because it is often nearly identical to its monomeric counterpart, differing by just a few mutations in a hinge region. Molecular dynamics (MD) simulations provide a computational method to sample different conformational states of a structure. Here, we tested whether MD simulations could be used as a post-design screening tool to identify sequence mutations leading to domain-swapped dimers. We hypothesized that a successful computationally-designed sequence would have backbone structure and dynamics characteristics similar to that of the input structure, and that in contrast, domain-swapped dimers would exhibit increased backbone flexibility and/or altered structure in the hinge-loop region to accommodate the large conformational change required for domain swapping. While attempting to engineer a homodimer from a 51 amino acid fragment of the monomeric protein engrailed homeodomain (ENH), we had instead generated a domainswapped dimer (ENH_DsD). MD simulations on these proteins showed increased MD simulation derived B factors in the hinge loop of the ENH_DsD domain-swapped dimer relative to monomeric ENH. Two point mutants of ENH_DsD designed to recover the monomeric fold were then tested with an MD simulation protocol. The MD simulations suggested that one of these mutants would adopt the target monomeric structure, which was subsequently confirmed by X-ray crystallography.

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“…There have been many experimental [1][2][3][4][5] and theoretical studies [6][7][8][9][10] aimed at designing enzymes to produce efficient catalysts for targeted reactions. Although this research area has seen significant progress in recent years, there is a great need for the development of new and improved methods to aid the design process.…”

Section: Introductionmentioning

confidence: 99%

Novel Approach for Identifying Key Residues in Enzymatic Reactions: Proton Abstraction in Ketosteroid Isomerase

Ito

Brinck

2014

J. Phys. Chem. B

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Abstract:We propose a computationally efficient approach for evaluating the individual contributions of many different residues to the catalytic efficiency of an enzymatic reaction.This approach is based on the fragment molecular orbital (FMO) method and it defines the energy of a deletion form, i.e. the energy of the system when a particular residue is deleted.Using this approach, we found that among ten investigated residues, three, Tyr14, Asp99, and Tyr55, in this order, significantly reduce the activation energy of the proton abstraction from a substrate, cyclopent-2-enone, catalyzed by ketosteroid isomerase (KSI). The relative activation energies estimated in this study are in good agreement with available previous experimental and theoretical data obtained for the similar proton abstraction with a native substrate and substitution mutants of KSI. It was thus indicated that the new approach is efficient for rationally evaluating the catalytic effects of multiple residues on an enzymatic reaction.

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Recent advances in computational protein design

Cited by 81 publications

References 57 publications

Advances in de novo strain design using integrated systems and synthetic biology tools

Advances in de novo strain design using integrated systems and synthetic biology tools

Using Molecular Dynamics Simulations as an Aid in the Prediction of Domain Swapping of Computationally Designed Protein Variants

Novel Approach for Identifying Key Residues in Enzymatic Reactions: Proton Abstraction in Ketosteroid Isomerase

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