scholarly journals Protein design by provable algorithms

2019 ◽  
Vol 62 (10) ◽  
pp. 76-84 ◽  
Author(s):  
Mark A. Hallen ◽  
Bruce R. Donald
Keyword(s):  
Protein Design ◽  
Provable Algorithms

scholarly journals Dynamics, a Powerful Component of Current and Future in Silico Approaches for Protein Design and Engineering

2020 ◽  
Vol 21 (8) ◽  
pp. 2713 ◽  
Author(s):  
Bartłomiej Surpeta ◽  
Carlos Eduardo Sequeiros-Borja ◽  
Jan Brezovsky
Keyword(s):  
Protein Design ◽  
In Silico ◽  
Computational Prediction ◽  
Computer Hardware ◽  
Conformational Ensembles ◽  
Tremendous Progress ◽  
Provable Algorithms ◽  
Realistic Description ◽  
Flexible Protein ◽  
Further Development

Computational prediction has become an indispensable aid in the processes of engineering and designing proteins for various biotechnological applications. With the tremendous progress in more powerful computer hardware and more efficient algorithms, some of in silico tools and methods have started to apply the more realistic description of proteins as their conformational ensembles, making protein dynamics an integral part of their prediction workflows. To help protein engineers to harness benefits of considering dynamics in their designs, we surveyed new tools developed for analyses of conformational ensembles in order to select engineering hotspots and design mutations. Next, we discussed the collective evolution towards more flexible protein design methods, including ensemble-based approaches, knowledge-assisted methods, and provable algorithms. Finally, we highlighted apparent challenges that current approaches are facing and provided our perspectives on their further development.

scholarly journals Novel, provable algorithms for efficient ensemble-based computational protein design and their application to the redesign of the c-Raf-RBD:KRas protein-protein interface

2020 ◽  
Vol 16 (6) ◽  
pp. e1007447 ◽  
Author(s):  
Anna U. Lowegard ◽  
Marcel S. Frenkel ◽  
Graham T. Holt ◽  
Jonathan D. Jou ◽  
Adegoke A. Ojewole ◽  
...  
Keyword(s):  
Protein Design ◽  
Computational Protein Design ◽  
Protein Interface ◽  
Provable Algorithms

scholarly journals Novel, provable algorithms for efficient ensemble-based computational protein design and their application to the redesign of the c-Raf-RBD:KRas protein-protein interface

2019 ◽  
Author(s):  
Anna U. Lowegard ◽  
Marcel S. Frenkel ◽  
Jonathan D. Jou ◽  
Adegoke A. Ojewole ◽  
Graham T. Holt ◽  
...  
Keyword(s):  
Protein Design ◽  
Input Sequence ◽  
Binding Domain ◽  
Computational Protein Design ◽  
Partition Functions ◽  
Protein Interface ◽  
Computational Structure ◽  
New Variant ◽  
Provable Algorithms ◽  
New Algorithms

AbstractThe K* algorithm provably approximates partition functions for a set of states (e.g., protein, ligand, and protein-ligand complex) to a user-specified accuracy ε. Often, reaching an ε-approximation for a particular set of partition functions takes a prohibitive amount of time and space. To alleviate some of this cost, we introduce two algorithms into the osprey suite for protein design: fries, a Fast Removal of Inadequately Energied Sequences, and EWAK*, an Energy Window Approximation to K*. In combination, these algorithms provably retain calculational accuracy while limiting the input sequence space and the conformations included in each partition function calculation to only the most energetically favorable. This combined approach leads to significant speed-ups compared to the previous state-of-the-art multi-sequence algorithm, BBK*. As a proof of concept, we used these new algorithms to redesign the protein-protein interface (PPI) of the c-Raf-RBD:KRas complex. The Ras-binding domain of the protein kinase c-Raf (c-Raf-RBD) is the tightest known binder of KRas, a historically “undruggable” protein implicated in difficult-to-treat cancers including pancreatic ductal adenocarcinoma (PDAC). fries/EWAK* accurately retrospectively predicted the effect of 38 out of 41 different sets of mutations in the PPI of the c-Raf-RBD:KRas complex. Notably, these mutations include mutations whose effect had previously been incorrectly predicted using other computational methods. Next, we used fries/EWAK* for prospective design and discovered a novel point mutation that improves binding of c-Raf-RBD to KRas in its active, GTP-bound state (KRasGTP). We combined this new mutation with two previously reported mutations (which were also highly-ranked by osprey) to create a new variant of c-Raf-RBD, c-Raf-RBD(RKY). fries/EWAK* in osprey computationally predicted that this new variant would bind even more tightly than the previous best-binding variant, c-Raf-RBD(RK). We measured the binding affinity of c-Raf-RBD(RKY) using a bio-layer interferometry (BLI) assay and found that this new variant exhibits single-digit nanomolar affinity for KRasGTP, confirming the computational predictions made with fries/EWAK*. This study steps through the advancement and development of computational protein design by presenting theory, new algorithms, accurate retrospective designs, new prospective designs, and biochemical validation.Author summaryComputational structure-based protein design is an innovative tool for redesigning proteins to introduce a particular or novel function. One such possible function is improving the binding of one protein to another, which can increase our understanding of biomedically important protein systems toward the improvement or development of novel therapeutics. Herein we introduce two novel, provable algorithms, fries and EWAK*, for more efficient computational structure-based protein design as well as their application to the redesign of the c-Raf-RBD:KRas protein-protein interface. These new algorithms speed up computational structure-based protein design while maintaining accurate calculations, allowing for larger, previously infeasible protein designs. Using fries and EWAK* within the osprey suite, we designed the tightest known binder of KRas, an “undruggable” cancer target. This new variant of a KRas-binding domain, c-Raf-RBD, should serve as an important tool to probe the protein-protein interface between KRas and its effectors as work continues toward an effective therapeutic targeting KRas.

Protein-design papers challenged

Nature ◽  
2009 ◽  
Author(s):  
Erika Check Hayden
Keyword(s):  
Protein Design

Automatic Procedures for Protein Design

2001 ◽  
Vol 4 (8) ◽  
pp. 643-659 ◽  
Author(s):  
Alfonso Jaramillo ◽  
Lorenz Wernisch ◽  
Stephanie Hery ◽  
Shosana Wodak
Keyword(s):  
Protein Design

scholarly journals Influence of protein (human galectin-3) design on aspects of lectin activity

2020 ◽  
Vol 154 (2) ◽  
pp. 135-153 ◽  
Author(s):  
Gabriel García Caballero ◽  
Donella Beckwith ◽  
Nadezhda V. Shilova ◽  
Adele Gabba ◽  
Tanja J. Kutzner ◽  
...  
Keyword(s):  
Protein Design ◽  
Full Range ◽  
Biological Information ◽  
The Novel ◽  
Modular Assembly ◽  
Binding Partners ◽  
Galectin 3 ◽  
Potential Applications ◽  
Similar Affinity

Abstract The concept of biomedical significance of the functional pairing between tissue lectins and their glycoconjugate counterreceptors has reached the mainstream of research on the flow of biological information. A major challenge now is to identify the principles of structure–activity relationships that underlie specificity of recognition and the ensuing post-binding processes. Toward this end, we focus on a distinct feature on the side of the lectin, i.e. its architecture to present the carbohydrate recognition domain (CRD). Working with a multifunctional human lectin, i.e. galectin-3, as model, its CRD is used in protein engineering to build variants with different modular assembly. Hereby, it becomes possible to compare activity features of the natural design, i.e. CRD attached to an N-terminal tail, with those of homo- and heterodimers and the tail-free protein. Thermodynamics of binding disaccharides proved full activity of all proteins at very similar affinity. The following glycan array testing revealed maintained preferential contact formation with N-acetyllactosamine oligomers and histo-blood group ABH epitopes irrespective of variant design. The study of carbohydrate-inhibitable binding of the test panel disclosed up to qualitative cell-type-dependent differences in sections of fixed murine epididymis and especially jejunum. By probing topological aspects of binding, the susceptibility to inhibition by a tetravalent glycocluster was markedly different for the wild-type vs the homodimeric variant proteins. The results teach the salient lesson that protein design matters: the type of CRD presentation can have a profound bearing on whether basically suited oligosaccharides, which for example tested positively in an array, will become binding partners in situ. When lectin-glycoconjugate aggregates (lattices) are formed, their structural organization will depend on this parameter. Further testing (ga)lectin variants will thus be instrumental (i) to define the full range of impact of altering protein assembly and (ii) to explain why certain types of design have been favored during the course of evolution, besides opening biomedical perspectives for potential applications of the novel galectin forms.

scholarly journals Searching for the Pareto frontier in multi-objective protein design

2017 ◽  
Vol 9 (4) ◽  
pp. 339-344 ◽  
Author(s):  
Vikas Nanda ◽  
Sandeep V. Belure ◽  
Ofer M. Shir
Keyword(s):  
Protein Design ◽  
Pareto Frontier ◽  
Multi Objective
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