Project 6: Computational design of microprotein binders for functional modulation (Danny Sahtoe)

ORFeus doctoral network; Utrecht; On-site; EUR 36,000 - 45,000; Full time

Job summary

The ORFeus consortium invites applications for a fully-funded 36-month MSCA doctoral position focused on AI-driven design of synthetic binders for microproteins. You will express and characterize target microproteins in E. coli, design high-affinity binders with AlphaFold3/RoseTTAfold, and iteratively optimize designs using structural data.

A secondment with an industry partner is included. You will contribute to a cross-disciplinary team, integrate data into the ORFeome platform, and enroll in

Qualifications

• Master's degree in life sciences or equivalent.
• Hands-on experience with recombinant protein expression and biophysical characterization.
• Experience with AI-based protein design tools and structure prediction is desirable.

Responsibilities

• Express a consortium-prioritized set of ~20 target microproteins in E. coli, purify and biophysically characterize them.
• Design high-affinity synthetic binders using AI design tools and folding models, refining designs via structural/biophysical feedback.
• Validate binder activity with biolayer interferometry and collaborate to confirm target modulation in cellular assays.
• Contribute binder library, models, and data to the ORFeome platform and participate in network activities.

Skills

Biochemistry

Structural biology

Biophysics

Molecular biology

Computational biology

Bioengineering

Protein expression

Protein purification

Biophysical characterization

Computational design

Structure prediction

AI protein design

Directed evolution

Yeast display

SEC-MALS

Biolayer interferometry

English proficiency

Interdisciplinary research

Travel willingness

Molecules microproteins

Education

Master's degree in life sciences

Tools

AlphaFold3

RoseTTAFold

MPNN

Job description

The position

Microproteins are small proteins translated from short stretches of the genome called small open reading frames (smORFs), which standard protein catalogs long overlooked. Many are now being discovered, but their biological roles remain largely unknown, and there are few tools to probe or control what they do. To study a microprotein's function, or to target it therapeutically, researchers need molecules that bind it selectively and switch its activity on or off, yet many microproteins are small and structurally disordered, so ready-made binders rarely exist.

This project will use AI-based protein design tools and folding models (AlphaFold3, RoseTTAFold) to create synthetic proteins that bind and modulate selected microproteins. You will express and characterize a consortium-prioritized set of around 20 target microproteins, design high-affinity binders for them, and refine those designs iteratively using structural and biophysical feedback. The work sits at the heart of ORFeus Work Package 2, which moves from discovery to function: it turns microproteins found by other projects into design targets and delivers the resulting binders as tools for functional and therapeutic studies across the network. It connects closely to partner projects on thermal proteome profiling, secreted and host-pathogen microproteins, and AI-driven prediction, which supply targets, prioritize the target list, and provide the structural and functional data that guide each design cycle.

Main tasks

• Express a consortium-prioritized set of around 20 target microproteins in E. coli, purify them, and characterize them biophysically using SEC-MALS and thermal stability assays.


• Design high-affinity synthetic binders using AI protein design tools and folding models (AlphaFold3, RoseTTAFold), refined iteratively through a feedback loop with structural and biophysical data from the project of another doctoral candidate (DC) in the network, here DC10 (thermal proteome profiling).


• Validate binder activity using biolayer interferometry and, in collaboration with DC5, functionally confirm that the binders modulate target activity in cellular assays.


• Contribute the binder library, structural models, and characterization data to the shared ORFeome platform, collaborate across the ORFeus network, and produce the project's scientific report.

Methods and platforms: AI-based computational protein design, recombinant protein expression in E. coli and purification, biophysical characterization (SEC-MALS, thermal stability assays, biolayer interferometry), directed evolution with yeast surface display, and cell-based functional assays, contributing designs and data to the ORFeome platform.

Secondment: you will spend around three months at an ORFeus industry partner, designing and optimizing synthetic protein binders for therapeutic targeting of microproteins. You will also be guided by an independent academic advisor, with the possibility of a short, primarily virtual research exchange to strengthen the project.

Your profile

MSCA eligibility

You must meet all of the following on your recruitment date:

• You do not already hold a doctoral degree. If you have defended a doctoral thesis but the degree has not yet been formally awarded, you are not eligible.


• Mobility rule: you must not have lived or carried out your main activity (work, studies, and so on) in the Netherlands for more than 12 months in the 36 months immediately before your recruitment date. Compulsory national service, short stays such as holidays, and time spent in a procedure to obtain refugee status under the Geneva Convention do not count toward the 12 months.


• You hold, or will hold before the start date, a degree that formally entitles you to enroll in a doctorate, and you can enroll in the doctoral program at the Hubrecht Institute / Utrecht University.

Candidates of any nationality may apply. There is no limit on prior research experience, as long as you do not already hold a doctorate.

Project-specific profile

• A master's degree (or equivalent) in biochemistry, structural biology, biophysics, molecular biology, computational biology, bioengineering, or a related life-science field.


• Hands-on experience with recombinant protein expression, purification, and biophysical characterization, and/or with computational protein structure prediction and design.


• Desirable: experience with AI-based protein design tools (for example MPNN, AlphaFold, RFdiffusion or similar), directed evolution or yeast surface display, biophysical methods such as SEC-MALS or biolayer interferometry, and an interest in microproteins and the dark proteome.


• Good written and spoken English.


• Motivation for interdisciplinary, collaborative research, and willingness to travel for the secondment and network events.

What we offer

A full-time employment contract for 36 months as a salaried researcher, with full social security coverage, under the rules of the Marie Skłodowska-Curie Actions. This is a paid employment contract, not a stipend or scholarship.

The salary has a living allowance and a mobility allowance, plus a family allowance if you have family obligations when you are recruited. The indicative gross salary for this position is between 3.204 - 4.051 euros gross per month. This is what you are paid before income tax and your own social-security contributions are deducted.

Beyond salary, you will receive:

• Supervision by a world-leading, interdisciplinary supervisory team.


• A secondment of around three months with an ORFeus industry partner.


• A structured training program: network-wide schools, transferable-skills training, workshops, and international conferences.


• Enrollment in a doctoral program leading to a PhD.


• Hubrecht to confirm host benefits, e.g. pension, paid leave, and relocation support. For all questions related to pension benefits, please refer to the Hubrecht Institute intranet page or contact the HR department for further information.

The MSCA employment contract covers 36 months of full-time, fully funded employment. In line with the host institution's doctoral policy, the host funds completion of the doctorate beyond the 36-month MSCA contract as continued employment at the standard national doctoral salary scale; terms confirmed at offer stage.

Working at the Hubrecht Institute

The Hubrecht Institute is a research institute of the Royal Netherlands Academy of Arts and Sciences (KNAW) in Utrecht, focused on molecular and developmental biology within a collaborative, international environment on the Utrecht Science Park.

You will join the group of Dr. Danny Sahtoe, which develops computationally designed protein systems to study and engineer biological systems. You will work closely with the group of Prof. Owen Rackham at the University of Southampton, who brings complementary computational biology and AI expertise, including machine-learning methods for the dark proteome. You will enroll as a PhD candidate at Graduate School of Life Sciences at Utrecht University, the degree-awarding partner of the Hubrecht Institute.