scholarly journals Dead-end elimination with perturbations (DEEPer): A provable protein design algorithm with continuous sidechain and backbone flexibility

2012 ◽  
Vol 81 (1) ◽  
pp. 18-39 ◽  
Author(s):  
Mark A. Hallen ◽  
Daniel A. Keedy ◽  
Bruce R. Donald
Keyword(s):  
Protein Design ◽  
Backbone Flexibility ◽  
Design Algorithm ◽  
Dead End

scholarly journals PLUG (Pruning of Local Unrealistic Geometries) removes restrictions on biophysical modeling for protein design

2018 ◽  
Author(s):  
Mark A. Hallen
Keyword(s):  
Protein Design ◽  
Conformational Space ◽  
Biophysical Model ◽  
Biophysical Modeling ◽  
Backbone Flexibility ◽  
Energy Functions ◽  
Design Algorithm ◽  
Dead End ◽  
Pruning Algorithms ◽  
Design Calculations

AbstractProtein design algorithms must search an enormous conformational space to identify favorable conformations. As a result, those that perform this search with guarantees of accuracy generally start with a conformational pruning step, such as dead-end elimination (DEE). However, the mathematical assumptions of DEE-based pruning algorithms have up to now severely restricted the biophysical model that can feasibly be used in protein design. To lift these restrictions, I propose to prune local unrealistic geometries (PLUG) using a linear programming-based method. PLUG’s biophysical model consists only of well-known lower bounds on interatomic distances. PLUG is intended as pre-processing for energy-based protein design calculations, whose biophysical model need not support DEE pruning. Based on 96 test cases, PLUG is at least as effective at pruning as DEE for larger protein designs—the type that most require pruning. When combined with the LUTE protein design algorithm, PLUG greatly facilitates designs that account for continuous entropy, large multistate designs with continuous flexibility, and designs with extensive continuous backbone flexibility and advanced non-pairwise energy functions. Many of these designs are tractable only with PLUG, either for empirical reasons (LUTE’s machine learning step achieves an accurate fit only after PLUG pruning), or for theoretical reasons (many energy functions are fundamentally incompatible with DEE).

scholarly journals Amino-acid site variability among natural and designed proteins

2013 ◽  
Author(s):  
Eleisha L. Jackson ◽  
Noah Ollikainen ◽  
Arthur W. Covert III ◽  
Tanja Kortemme ◽  
Claus O. Wilke
Keyword(s):  
Amino Acid ◽  
Protein Design ◽  
Protein Sequences ◽  
Structural Constraints ◽  
Scoring Functions ◽  
Solvent Exposure ◽  
Backbone Flexibility ◽  
Hydrophobic Residues ◽  
Designed Proteins ◽  
Site Variability

Computational protein design attempts to create protein sequences that fold stably into pre-specified structures. Here we compare alignments of designed proteins to alignments of natural proteins and assess how closely designed sequences recapitulate patterns of sequence variation found in natural protein sequences. We design proteins using RosettaDesign, and we evaluate both fixed-backbone designs and variable-backbone designs with different amounts of backbone flexibility. We find that proteins designed with a fixed backbone tend to underestimate the amount of site variability observed in natural proteins while proteins designed with an intermediate amount of backbone flexibility result in more realistic site variability. Further, the correlation between solvent exposure and site variability in designed proteins is lower than that in natural proteins. This finding suggests that site variability is too uniform across different solvent exposure states (i.e., buried residues are too variable or exposed residues too conserved). When comparing the amino acid frequencies in the designed proteins with those in natural proteins we find that in the designed proteins hydrophobic residues are underrepresented in the core. From these results we conclude that intermediate backbone flexibility during design results in more accurate protein design and that either scoring functions or backbone sampling methods require further improvement to accurately replicate structural constraints on site variability.

scholarly journals Positive multistate protein design

2019 ◽  
Vol 36 (1) ◽  
pp. 122-130
Author(s):  
Jelena Vucinic ◽  
David Simoncini ◽  
Manon Ruffini ◽  
Sophie Barbe ◽  
Thomas Schiex
Keyword(s):  
Protein Design ◽  
Critical Role ◽  
Average Energy ◽  
Computational Design ◽  
Amino Acid Sequences ◽  
Supplementary Information ◽  
Backbone Flexibility ◽  
Identify Amino Acid ◽  
Design Software ◽  
Protein Redesign

Abstract Motivation Structure-based computational protein design (CPD) plays a critical role in advancing the field of protein engineering. Using an all-atom energy function, CPD tries to identify amino acid sequences that fold into a target structure and ultimately perform a desired function. The usual approach considers a single rigid backbone as a target, which ignores backbone flexibility. Multistate design (MSD) allows instead to consider several backbone states simultaneously, defining challenging computational problems. Results We introduce efficient reductions of positive MSD problems to Cost Function Networks with two different fitness definitions and implement them in the Pompd (Positive Multistate Protein design) software. Pompd is able to identify guaranteed optimal sequences of positive multistate full protein redesign problems and exhaustively enumerate suboptimal sequences close to the MSD optimum. Applied to nuclear magnetic resonance and back-rubbed X-ray structures, we observe that the average energy fitness provides the best sequence recovery. Our method outperforms state-of-the-art guaranteed computational design approaches by orders of magnitudes and can solve MSD problems with sizes previously unreachable with guaranteed algorithms. Availability and implementation https://forgemia.inra.fr/thomas.schiex/pompd as documented Open Source. Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals Computational protein design with backbone plasticity

2016 ◽  
Vol 44 (5) ◽  
pp. 1523-1529 ◽  
Author(s):  
James T. MacDonald ◽  
Paul S. Freemont
Keyword(s):  
Protein Design ◽  
De Novo ◽  
Protein Structures ◽  
Search Space ◽  
Computational Protein Design ◽  
Artificial Enzymes ◽  
Backbone Flexibility ◽  
Artificial Proteins ◽  
Naturally Occurring ◽  
Backbone Structure

The computational algorithms used in the design of artificial proteins have become increasingly sophisticated in recent years, producing a series of remarkable successes. The most dramatic of these is the de novo design of artificial enzymes. The majority of these designs have reused naturally occurring protein structures as ‘scaffolds’ onto which novel functionality can be grafted without having to redesign the backbone structure. The incorporation of backbone flexibility into protein design is a much more computationally challenging problem due to the greatly increased search space, but promises to remove the limitations of reusing natural protein scaffolds. In this review, we outline the principles of computational protein design methods and discuss recent efforts to consider backbone plasticity in the design process.

scholarly journals De novo protein design enables precise induction of functional antibodies in vivo

2019 ◽  
Author(s):  
Fabian Sesterhenn ◽  
Che Yang ◽  
Jaume Bonet ◽  
Johannes T Cramer ◽  
Xiaolin Wen ◽  
...  
Keyword(s):  
Protein Design ◽  
De Novo ◽  
Antibody Responses ◽  
Design Algorithm ◽  
De Novo Protein Design ◽  
Complex Structural ◽  
Syncytial Virus ◽  
Functional Antibodies ◽  
Novel Protein

AbstractDe novo protein design has been successful in expanding the natural protein repertoire. However, most de novo proteins lack biological function, presenting a major methodological challenge. In vaccinology, the induction of precise antibody responses remains a cornerstone for next-generation vaccines. Here, we present a novel protein design algorithm, termed TopoBuilder, with which we engineered epitope-focused immunogens displaying complex structural motifs. Both in mice and non-human primates, cocktails of three de novo designed immunogens induced robust neutralizing responses against the respiratory syncytial virus. Furthermore, the immunogens refocused pre-existing antibody responses towards defined neutralization epitopes. Overall, our de novo design approach opens the possibility of targeting specific epitopes for vaccine and therapeutic antibody development, and more generally will be applicable to design de novo proteins displaying complex functional motifs.

scholarly journals Amino-acid site variability among natural and designed proteins

2013 ◽  
Author(s):  
Eleisha L. Jackson ◽  
Noah Ollikainen ◽  
Arthur W. Covert III ◽  
Tanja Kortemme ◽  
Claus O. Wilke
Keyword(s):  
Amino Acid ◽  
Protein Design ◽  
Protein Sequences ◽  
Structural Constraints ◽  
Scoring Functions ◽  
Solvent Exposure ◽  
Backbone Flexibility ◽  
Hydrophobic Residues ◽  
Designed Proteins ◽  
Site Variability

Computational protein design attempts to create protein sequences that fold stably into pre-specified structures. Here we compare alignments of designed proteins to alignments of natural proteins and assess how closely designed sequences recapitulate patterns of sequence variation found in natural protein sequences. We design proteins using RosettaDesign, and we evaluate both fixed-backbone designs and variable-backbone designs with different amounts of backbone flexibility. We find that proteins designed with a fixed backbone tend to underestimate the amount of site variability observed in natural proteins while proteins designed with an intermediate amount of backbone flexibility result in more realistic site variability. Further, the correlation between solvent exposure and site variability in designed proteins is lower than that in natural proteins. This finding suggests that site variability is too uniform across different solvent exposure states (i.e., buried residues are too variable or exposed residues too conserved). When comparing the amino acid frequencies in the designed proteins with those in natural proteins we find that in the designed proteins hydrophobic residues are underrepresented in the core. From these results we conclude that intermediate backbone flexibility during design results in more accurate protein design and that either scoring functions or backbone sampling methods require further improvement to accurately replicate structural constraints on site variability.

scholarly journals Rational Design of SARS-CoV-2 Spike Glycoproteins To Increase Immunogenicity By T Cell Epitope Engineering

2020 ◽  
Author(s):  
Edison Ong ◽  
Xiaoqiang Huang ◽  
Robin Pearce ◽  
Yang Zhang ◽  
Yongqun He
Keyword(s):  
T Cell ◽  
Protein Design ◽  
Rational Design ◽  
Cell Epitope ◽  
Structural Similarity ◽  
T Cell Response ◽  
Design Algorithm ◽  
S Protein ◽  
Mhc Ii ◽  
Structural Vaccinology

AbstractThe current COVID-19 pandemic caused by SARS-CoV-2 has resulted in millions of confirmed cases and thousands of deaths globally. Extensive efforts and progress have been made to develop effective and safe vaccines against COVID-19. A primary target of these vaccines is the SARS-CoV-2 spike (S) protein, and many studies utilized structural vaccinology techniques to either stabilize the protein or fix the receptor-binding domain at certain states. In this study, we extended an evolutionary protein design algorithm, EvoDesign, to create thousands of stable S protein variants without perturbing the surface conformation and B cell epitopes of the S protein. We then evaluated the mutated S protein candidates based on predicted MHC-II T cell promiscuous epitopes as well as the epitopes’ similarity to human peptides. The presented strategy aims to improve the S protein’s immunogenicity and antigenicity by inducing stronger CD4 T cell response while maintaining the protein’s native structure and function. The top EvoDesign S protein candidate (Design-10705) recovered 31 out of 32 MHC-II T cell promiscuous epitopes in the native S protein, in which two epitopes were present in all seven human coronaviruses. This newly designed S protein also introduced nine new MHC-II T cell promiscuous epitopes and showed high structural similarity to its native conformation. The proposed structural vaccinology method provides an avenue to rationally design the antigen’s structure with increased immunogenicity, which could be applied to the rational design of new COVID-19 vaccine candidates.

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