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Simultaneous enhancement of multiple functional properties using evolution-informed protein design.

ABSTRACT: A major challenge in protein design is to augment existing functional proteins with multiple property enhancements. Altering several properties likely necessitates numerous primary sequence changes, and novel methods are needed to accurately predict combinations of mutations that maintain or enhance function. Models of sequence co-variation (e.g., EVcouplings), which leverage extensive information about various protein properties and activities from homologous protein sequences, have proven effective for many applications including structure determination and mutation effect prediction. We apply EVcouplings to computationally design variants of the model protein TEM-1 β-lactamase. Nearly all the 14 experimentally characterized designs were functional, including one with 84 mutations from the nearest natural homolog. The designs also had large increases in thermostability, increased activity on multiple substrates, and nearly identical structure to the wild type enzyme. This study highlights the efficacy of evolutionary models in guiding large sequence alterations to generate functional diversity for protein design applications.

SUBMITTER: Fram B

PROVIDER: S-EPMC11190266 | biostudies-literature | 2024 Jun

REPOSITORIES: biostudies-literature

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Simultaneous enhancement of multiple functional properties using evolution-informed protein design.

Fram Benjamin B Su Yang Y Truebridge Ian I Riesselman Adam J AJ Ingraham John B JB Passera Alessandro A Napier Eve E Thadani Nicole N NN Lim Samuel S Roberts Kristen K Kaur Gurleen G Stiffler Michael A MA Marks Debora S DS Bahl Christopher D CD Khan Amir R AR Sander Chris C Gauthier Nicholas P NP

Nature communications 20240620 1

A major challenge in protein design is to augment existing functional proteins with multiple property enhancements. Altering several properties likely necessitates numerous primary sequence changes, and novel methods are needed to accurately predict combinations of mutations that maintain or enhance function. Models of sequence co-variation (e.g., EVcouplings), which leverage extensive information about various protein properties and activities from homologous protein sequences, have proven effe ...[more]

PMID: 38902262

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Project description:BackgroundThe development of technological applications in clinical research, such as electronic informed consent (eIC), is on the rise. The involvement of end users throughout the design process of eIC is of utmost importance to improve the current informed consent process.MethodsUsing a provocative design, we conducted interviews with 30 clinical research participants. Provotypes were used as a starting base to discuss various aspects relevant to eIC. By providing a medium to encourage divergent thinking, participants' views and concerns were solicited. Thematic analysis was undertaken using NVivo.ResultsThe majority of participants placed trust in the principal investigator or the hospital to perform the role of eIC hosting party. Differing opinions were reported on the amount of information required related to stakeholders' access to an eIC system, and thus, to participants' personal data, to enable trust in an eIC system. Nevertheless, this study indicates a general willingness of participants to share personal data with physicians and pharmaceutical companies on an international level, and to receive requests for new research studies via an eIC system. Participants suggested to tailor an eIC system based upon their preferences, for example, regarding whom they want to share their personal data with. Moreover, they expressed a desire to choose how they can contact the research team, and to indicate which study-related information they would like to receive electronically. In addition, positive opinions were voiced on the integration of a test to assess participants' understanding before providing their eIC.ConclusionsFollowing a research through design approach, insights have been generated which inform the design of eIC. Provotypes were designed to help participants think beyond what is familiar to them. Study findings revealed that not all situations were perceived as provocative, because of participants' motivation to advance scientific research and the trust they place in the research team. Nevertheless, the use of provocative design resulted in additional insights, generated by clinical research participants, which could be considered in the further design of eIC.

Dataset Information

Simultaneous enhancement of multiple functional properties using evolution-informed protein design.

Publications

Simultaneous enhancement of multiple functional properties using evolution-informed protein design.

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