Fast yet accurate routine rational design of novel enzymes

Introduction

Life could not be sustained without the presence of enzymes, which are responsible for accelerating the chemical reactions in a biologically compatible timescale. Enzymes present other advantageous features such as high specificity and selectivity, plus they operate under very mild biological conditions.

Motivation

Inspired by these extraordinary characteristics, many scientists wondered about the possibility of designing new enzymes for industrially relevant targets. Unfortunately, none of the current enzyme design strategies is able to rapidly design tailor-made enzymes at a reduced cost. This limitation affects the general routine application of enzyme catalysis in industry, thus impacting chemical manufacturing competitiveness.

Project Goal

The goal of this project is to develop a fast yet accurate computational enzyme design approach for allowing the routine design of highly efficient enzymes.

Methodology

FASTEN combines several advanced techniques:

• Computational chemistry
• Deep learning
• Graph theory
• Computational geometry

These techniques are used for controlling the complexity of enzyme catalysis in a new computational protocol that will capture the chemical steps and conformational changes that take place along the catalytic itinerary.

Design Predictions

Active site and distal activity-enhancing mutations are predicted based on correlation and co-evolutionary-based guidelines. The catalytic potential of the new designs is estimated by means of geometry-based oracles.

Validation

This new computational approach will be validated with the design of enzymes presenting complex conformational dynamics and multi-step mechanisms. The experimental evaluation of many of the designs will finally reveal the potential of this new approach for the fast routine design of industrially relevant enzymes.

Impact

FASTEN has the potential of making the routine design of enzymes possible, thus improving our current lives and leading to a more sustainable world for our generations.