D-peptides, the mirror image of canonical L-peptides, offer numerous biological advantages that make them effective therapeutics. This article details how to use DexDesign, the newest OSPREY-based algorithm, for designing these D-peptides de novo. OSPREY physics-based models precisely mimic energy-equivariant reflection operations, enabling the generation of D-peptide scaffolds from L-peptide templates. Due to the scarcity of D-peptide:L-protein structural data, DexDesign calls a geometric hashing algorithm, Method of Accelerated Search for Tertiary Ensemble Representatives, as a subroutine to produce a synthetic structural dataset. DexDesign enables mixed-chirality designs with a new user interface and also reduces the conformation and sequence search space using three new design techniques: Minimum Flexible Set, Inverse Alanine Scanning, and K*-based Mutational Scanning.
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References
1.
AngeliniA, CendronL, ChenS, et al.Bicyclic peptide inhibitor reveals large contact interface with a protease target. ACS Chem Biol, 2012; 7(5):817–821; doi: 10.1021/cb200478t
2.
BenkiraneN, FriedeM, GuichardG, et al.Antigenicity and immunogenicity of modified synthetic peptides containing D-Amino acid residues. Antibodies to a D-Enantiomer do recognize the parent L-Hexapeptide and reciprocally. J Biol Chem, 1993; 268(35):26279–26285.
3.
BhardwajG, MulliganVK, BahlCD, et al.Accurate de novo design of hyperstable constrained peptides. Nature, 2016; 538(7625):329–335; doi: 10.1038/nature19791
ChenC-Y, GeorgievI, AndersonAC, et al.Computational structure-based redesign of enzyme activity. Proc Natl Acad Sci U S A, 2009; 106(10):3764–3769; doi: 10.1073/pnas.0900266106
6.
CraikDJ, FairlieDP, LirasS, et al.The future of peptide-based drugs. Chem Biol Drug Des, 2013; 81(1):136–147; doi: 10.1111/cbdd.12055
DonaldBR. Algorithms in Structural Molecular Biology. MIT Press; 2011.
9.
ElkinCD, ZuccolaHJ, HogleJM, et al.Computational design of D-Peptide inhibitors of hepatitis delta antigen dimerization. J Comput Aided Mol Des, 2000; 14(8):705–718; doi: 10.1023/a:1008146015629
10.
FreyKM, GeorgievI, DonaldBR, et al.Predicting resistance mutations using protein design algorithms. Proc Natl Acad Sci U S A, 2010; 107(31):13707–13712.
11.
GainzaP, RobertsKE, DonaldBR. Protein design using continuous rotamers. PLoS Comput Biol, 2012; 8(1):e1002335; doi: 10.1371/journal.pcbi.1002335
12.
GartonM, SayadiM, KimPM. A computational approach for designing D-Proteins with non-canonical amino acid optimised binding affinity. PLoS One, 2017; 12(11):e0187524; doi: 10.1371/journal.pone.0187524
13.
GeorgievI, LilienRH, DonaldBR. The minimized dead-end elimination criterion and its application to protein redesign in a hybrid scoring and search algorithm for computing partition functions over molecular ensembles. J Comput Chem, 2008; 29(10):1527–1542; doi: 10.1002/jcc.20909
14.
GuerinN, ChildsH, ZhouP, et al.DexDesign: An OSPREY-based algorithm for designing de Novo D-Peptide inhibitors. Protein Eng Des Sel, 2024; 37 Accepted, In Press.
15.
HallenMA, DonaldBR. CATS (Coordinates of Atoms by Taylor Series): Protein design with backbone flexibility in all locally feasible directions. Bioinformatics, 2017; 33(14):i5–i12.
16.
HallenMA, DonaldBR. COMETS (Constrained Optimization of Multistate Energies by Tree Search): A provable and efficient protein design algorithm to optimize binding affinity and specificity with respect to sequence. J Comput Biol, 2016; 23(5):311–321.
17.
HallenMA, DonaldBR. Protein design by provable algorithms. Commun ACM, 2019; 62(10):76–84; doi: 10.1145/3338124
18.
HallenMA, KeedyDA, DonaldBR. Dead-End elimination with perturbations (DEEPer): A provable protein design algorithm with continuous sidechain and backbone flexibility. Proteins Struct Funct Bioinforma, 2013; 81(1):18–39.
19.
HallenMA, MartinJW, OjewoleA, et al.OSPREY 3.0: Open-source protein redesign for you, with powerful new features. J Comput Chem, 2018; 39(30):2494–2507; doi: 10.1002/jcc.25522
20.
HoltGT, GormanJ, WangS, et al.Improved HIV-1 Neutralization breadth and potency of V2-apex antibodies by in silico design. Cell Rep, 2023; 42(7):112711; doi: 10.1016/j.celrep.2023.112711
21.
JainS, JouJD, GeorgievIS, et al.A critical analysis of computational protein design with sparse residue interaction graphs. PLoS Comput Biol, 2017; 13(3):e1005346; doi: 10.1371/journal.pcbi.1005346
22.
JouJD, GuerinN, RobertsKE. Protein Design Plugin. 2023.
23.
JouJD, HoltGT, LowegardAU, et al.Minimization-aware recursive K*: A novel, provable algorithm that accelerates ensemble-based protein design and provably approximates the energy landscape. J Comput Biol, 2020; 27(4):550–564; doi: 10.1089/cmb.2019.0315
24.
JouJD, JainS, GeorgievIS, et al.BWM*: A novel, provable, ensemble-based dynamic programming algorithm for sparse approximations of computational protein design. J Comput Biol, 2016; 23(6):413–424; doi: 10.1089/cmb.2015.0194
25.
KabschW. A discussion of the solution for the best rotation to relate two sets of vectors. Acta Cryst A, 1978; 34(5):827–828; doi: 10.1107/S0567739478001680
26.
KabschW. A solution for the best rotation to relate two sets of vectors. Acta Cryst A, 1976; 32(5):922–923; doi: 10.1107/S0567739476001873
27.
LilienRH, StevensBW, AndersonAC, et al.A novel ensemble-based scoring and search algorithm for protein redesign and its application to modify the substrate specificity of the gramicidin synthetase a phenylalanine adenylation enzyme. J Comput Biol, 2005; 12(6):740–761.
28.
LowegardA. Novel Algorithms and Tools for Computational Protein Design with Applications to Drug Resistance Prediction, Antibody Design, Peptide Inhibitor Design, and Protein Stability Prediction. PhD Thesis. Duke University; 2019.
NisonoffH. Efficient Partition Function Estimation in Computational Protein Design: Probabalistic Guarantees and Characterization of a Novel Algorithm. Bachelor’s Thesis. Duke University; 2015.
31.
NoetherE. Gesammelte Abhandlungen–Collected Papers. 1st ed. Springer Collected Works in Mathematics. Springer Berlin, Heidelberg: Berlin; 1983.
32.
OjewoleAA, JouJD, FowlerVG, et al.BBK* (Branch and Bound Over K*): A provable and efficient ensemble-based protein design algorithm to optimize stability and binding affinity over large sequence spaces. J Comput Biol, 2018; 25(7):726–739; doi: 10.1089/cmb.2017.0267
33.
ReeveSM, GainzaP, FreyKM, et al.Protein design algorithms predict viable resistance to an experimental antifolate. Proc Natl Acad Sci U S A, 2015; 112(3):749–754.
34.
RenfrewPD, ChoiEJ, BonneauR, et al.Incorporation of noncanonical amino acids into rosetta and use in computational protein-peptide interface design. PLoS One, 2012; 7(3):e32637; doi: 10.1371/journal.pone.0032637
35.
SchrödingerLLC. The PyMOL Molecular Graphics System, Version 1.8. 2015.
36.
StevensBW, LilienRH, GeorgievI, et al.Redesigning the PheA domain of Gramicidin synthetase leads to a new understanding of the Enzyme’s mechanism and selectivity. Biochemistry, 2006; 45(51):15495–15504; doi: 10.1021/bi061788m
37.
WangS. Computational Protein Design with Non-Proteinogenic Amino Acids and Small Molecule Ligands, with Applications to Protein-Protein Interaction Inhibitors, Anti-Microbial Enzyme Inhibitors, and Antibody Design. Duke University; 2021.
38.
WangS, ReeveSM, HoltGT, et al.Chiral evasion and stereospecific antifolate resistance in Staphylococcus aureus. PLoS Comput Biol, 2022; 18(2):e1009855; doi: 10.1371/journal.pcbi.1009855
39.
WordJM, LovellSC, LaBeanTH, et al.Visualizing and quantifying molecular goodness-of-fit: Small-probe contact dots with explicit hydrogen atoms1. J Mol Biol, 1999; 285(4):1711–1733; doi: 10.1006/jmbi.1998.2400
40.
ZhouJ, GrigoryanG. Rapid search for tertiary fragments reveals protein sequence–structure relationships. Protein Sci, 2015; 24(4):508–524; doi: 10.1002/pro.2610
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