Roberto Chica Lab

In our latest preprint, we introduce Multistate Enzyme Design, a computational framework that simultaneously optimizes enzyme sequences across multiple transition states while preserving the conformational flexibility needed to access them. www.biorxiv.org/content/10.6...

Our work proposes a shift in enzyme design: instead of optimizing a single transition state, we can make the entire reaction coordinate the design objective. Huge thanks to Anthony Green (Manchester), Mike Thompson (UC Merced), and Sam Hay (Manchester) for a fantastic collaboration!

In our latest preprint, we introduce Multistate Enzyme Design, a computational framework that simultaneously optimizes enzyme sequences across multiple transition states while preserving the conformational flexibility needed to access them. www.biorxiv.org/content/10.6...

Why does it work? Structural analyses show that multistate design preserves an active site compatible with multiple transition states, whereas single-state optimization does not.

In our latest preprint, we introduce Multistate Enzyme Design, a computational framework that simultaneously optimizes enzyme sequences across multiple transition states while preserving the conformational flexibility needed to access them. www.biorxiv.org/content/10.6...

Instead of designing a static active site, we design for a dynamic reaction coordinate. To test the idea, we redesigned the evolved de novo Morita-Baylis-Hillmanase BH32.12, a four-step carbon-carbon bond-forming enzyme.

1/6 Thrilled to announce our updated preprint on the CANVAS method for de novo enzyme design, in collaboration with @birtehoecker.bsky.social. We show how CANVAS builds custom lids onto minimal TIM barrels, transforming them into efficient catalysts. www.biorxiv.org/content/10.1...

5/6 Molecular dynamics simulations helped dissect structural determinants of catalysis. Our catalytic‑competency score, i.e. the fraction of snapshots with both key catalytic contacts formed, tracks well with experimental activity across variants.

1/6 Thrilled to announce our updated preprint on the CANVAS method for de novo enzyme design, in collaboration with @birtehoecker.bsky.social. We show how CANVAS builds custom lids onto minimal TIM barrels, transforming them into efficient catalysts. www.biorxiv.org/content/10.1...

3/6 We solved the KempTIM1 crystal structure (blue) bound to a transition‑state analogue. The designed lid (magenta) shows excellent agreement with the model, and the ligand binds in a similar pose to the design model, enabling the intended catalytic contacts.

1/6 Thrilled to announce our updated preprint on the CANVAS method for de novo enzyme design, in collaboration with @birtehoecker.bsky.social. We show how CANVAS builds custom lids onto minimal TIM barrels, transforming them into efficient catalysts. www.biorxiv.org/content/10.1...

1/ Save the date! The 6th Protein Engineering Canada Conference will be held on June 22-24 in Ottawa, Canada. Abstract submission and registration are open! More information here: event.fourwaves.com/pec2026/pages

In collaboration with @birtehoecker.bsky.social, we’ve unlocked enzymatic activity in a minimal de novo TIM barrel by designing a custom lid for catalysis! 🧵👇 #ProteinDesign #EnzymeDesign Customizing the Structure of a Minimal TIM Barrel to Create a De Novo Enzyme www.biorxiv.org/content/10.1...

Our crystal structure validated the designed fold, confirming that the lid was correctly folded. However, a subtle 1.8 Å lid shift disrupted a key catalytic contact, likely contributing to the modest activity. But structural analysis reveals paths to improve activity in the next round of design!

In collaboration with @birtehoecker.bsky.social, we’ve unlocked enzymatic activity in a minimal de novo TIM barrel by designing a custom lid for catalysis! 🧵👇 #ProteinDesign #EnzymeDesign Customizing the Structure of a Minimal TIM Barrel to Create a De Novo Enzyme www.biorxiv.org/content/10.1...

Using CANVAS, we designed a structural lid onto a minimal, de novo TIM barrel to anchor catalytic residues and create an active site for the Kemp elimination reaction.

In collaboration with @birtehoecker.bsky.social, we’ve unlocked enzymatic activity in a minimal de novo TIM barrel by designing a custom lid for catalysis! 🧵👇 #ProteinDesign #EnzymeDesign Customizing the Structure of a Minimal TIM Barrel to Create a De Novo Enzyme www.biorxiv.org/content/10.1...

How do mutations far from an enzyme's active site influence catalysis? 🤔 Part 2: In collaboration with @fraserlab.bsky.social and @silviaosuna.bsky.social, we investigated this question using de novo Kemp eliminases, revealing effects of distal mutations on the catalytic cycle. 🧵 (1/6)

Molecular dynamics simulations showed that distal mutations enhance active-site accessibility—either by loosening loops covering the active site or widening bottlenecks for substrate entry & product exit. The enzyme breathes more efficiently! 🌬️ (5/6)

How do mutations far from an enzyme's active site influence catalysis? 🤔 Part 2: In collaboration with @fraserlab.bsky.social and @silviaosuna.bsky.social, we investigated this question using de novo Kemp eliminases, revealing effects of distal mutations on the catalytic cycle. 🧵 (1/6)

Crystal structures showed that active-site mutations pre-organize the catalytic machinery. But distal mutations? They subtly tune conformational dynamics—enhancing productive substates & reshaping the energy landscape of the catalytic cycle. (3/6)

How do mutations far from an enzyme's active site influence catalysis? 🤔 Part 2: In collaboration with @fraserlab.bsky.social and @silviaosuna.bsky.social, we investigated this question using de novo Kemp eliminases, revealing effects of distal mutations on the catalytic cycle. 🧵 (1/6)