[Mayo lecture summary] Part 1 Protein Design by Computation

In this lecture, Prof. Mayo introduces basic concept of computational protein design and methods with exemplar processes.

• Protein Fold Prediction vs Protein Design

Protein fold prediction is about prediction of protein structure based on sequence while protein design is about prediction of protein sequence which has a desired function

• Methods of Computational Protein Design
  

Protein backbones typically come from PDB.
Due to conformational flexiblity, rotamer libraries are considered.

Building atom-based forcefields are important for accurate protein design.

With these backbone, rotamer, forcefields issues, combinatorial optimization algorithms are used for calculation.

Negative design is about a protein that prevents a certain function (ex. unwanted aggregation).

• Design Process Flow
  

1. Specify design objectives
2. Computationally design AA sequence using ORBIT
3. Assemble gene for new protein
4. Express gene in favorite host
5. Isolate and purify protein
6. Evaluate properties of designed protein
7. Iterate design

(these processes are similar to my QSAR experiences regarding that to accurately model some biological/chemical responses, iterative modification of modeling techniques is exploited)

• Sample Energy Calculation
  

To design a protein sequence which will bring a desired function, energy calculation is needed.

As a simple example (one body interaction such as the interaction between AA and backbone), many types of the energy between two AA are calculated such as van der waals force, electrostatic interaction (coulomb potential), hydrogen bond (direction specified), and solvation potential (penalize the exposure to hydrophobic surface area or polar surface area depending on design purpose).

Two body interaction is about the interaction between pairs (such as the interaction between the AAs).

Finally, the combinatorial energy is calculated as a following example, the combinatorial energy of Ser3 at position 1 and Ser2 at position 2 (-9.0) is a sum of 2 one body energy (-0.4, -3.1) and 1 two body energy (-5.5).

Among these combinatorial energies, the lowest energy is selected.

source: http://www.youtube.com/watch?v=a8CVm5S35ko