This study presents an enhanced protein design algorithm that aims to emulate natural heterogeneity of protein sequences. Initial analysis revealed that natural proteins exhibit a permutation composition lower than the theoretical maximum, suggesting a selective utilization of the 20-letter amino acid alphabet. By not constraining the amino acid composition of the protein sequence but instead allowing random reshuffling of the composition, the resulting design algorithm generates sequences that maintain lower permutation compositions in equilibrium, aligning closely with natural proteins. Folding free energy computations demonstrated that the designed sequences refold to their native structures with high precision, except for proteins with large disordered regions. In addition, direct coupling analysis showed a strong correlation between predicted and actual protein contacts, with accuracy exceeding 82% for a large number of top pairs (L). The algorithm also resolved biases in previous designs, ensuring a more accurate representation of protein interactions. Overall, it not only mimics the natural heterogeneity of proteins but also ensures correct folding, marking a significant advancement in protein design and engineering.
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21 November 2024
Research Article|
November 15 2024
Designing proteins: Mimicking natural protein sequence heterogeneity
Special Collection:
Monte Carlo methods, 70 years after Metropolis et al. (1953)
Marcos Lequerica-Mateos
;
Marcos Lequerica-Mateos
(Data curation, Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review & editing)
1
Fundación BCMaterials, UPV/EHU
, Leioa, Spain
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Jonathan Martin
;
Jonathan Martin
(Data curation, Formal analysis, Investigation, Methodology, Visualization, Writing – original draft, Writing – review & editing)
2
Department of Biological Sciences, University of Texas at Dallas
, Richardson, Texas 75080, USA
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José N. Onuchic
;
José N. Onuchic
a)
(Conceptualization, Funding acquisition, Methodology, Project administration, Resources, Supervision, Writing – original draft, Writing – review & editing)
3
Center for Theoretical Biological Physics, Rice University
, Houston, Texas 77005, USA
4
Department of Physics and Astronomy, Department of Chemistry, Department of BioSciences, Rice University
, Houston, Texas 77005, USA
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Faruck Morcos
;
Faruck Morcos
b)
(Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Supervision, Writing – original draft, Writing – review & editing)
2
Department of Biological Sciences, University of Texas at Dallas
, Richardson, Texas 75080, USA
5
Departments of Bioengineering, Physics and Center for Systems Biology, University of Texas at Dallas
, Richardson, Texas 75080, USA
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Ivan Coluzza
Ivan Coluzza
c)
(Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing)
3
Center for Theoretical Biological Physics, Rice University
, Houston, Texas 77005, USA
c)Author to whom correspondence should be addressed: [email protected]
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c)Author to whom correspondence should be addressed: [email protected]
a)
Electronic mail: [email protected]
b)
Electronic mail: [email protected]
J. Chem. Phys. 161, 194102 (2024)
Article history
Received:
August 10 2024
Accepted:
October 18 2024
Citation
Marcos Lequerica-Mateos, Jonathan Martin, José N. Onuchic, Faruck Morcos, Ivan Coluzza; Designing proteins: Mimicking natural protein sequence heterogeneity. J. Chem. Phys. 21 November 2024; 161 (19): 194102. https://doi.org/10.1063/5.0232831
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