The document discusses the necessity of protein minimization for molecular docking, highlighting its distinction from protein preparation and addressing various concerns like crystal artefacts and the impact of bound ligands. It emphasizes the importance of optimizing hydrogen positions and provides key steps for effective protein preparation, including the assessment of alternate conformations and the definition of cofactors. The document concludes with encouraging online teaching and the integration of human expertise with computational tools.

1. Protein Minimization
required or not
for Molecular Docking?
Girinath G Pillai, PhD
@giribio

2. ● Slides contains contents/pictures/videos taken from web, articles,
lectures, tutorials and its respective authors own their copyrights.
Technical Slides : slideshare.net/giribio
Case Studies : youtube.com/giribio
Workflows & Notebooks : github.com/giribio

3. Protein minimisation &
Protein preparation
Are not same!

4. The Concerns!
Assumptions
● FF better describes
the geometry than the
the other structures?
● Eliminate
crystal-packing
artifacts
Optimization
● Adding missing
residues if any and
then minimization is
required
● FF being used is
different from that
used to optimise the
PDB from X-Ray data
Preparation
● Making protein more
suitable for
computational expts.
● Optimise the
directions that the
hydrogen are facing
and then reproduce
the crystal structure if
it has a bound ligand

5. Factors to consider
Crystal Structures
Minimize or not?
High resolution crystal
structures - (If Electron density is
perfectly fitted to AA coordinates,
protein minimization is not required.)
Optimize positions of
hydrogens which are added to
crystal structures
Freeze or constrain all of the
heavy atoms and only
minimize the hydrogens
No bound ligands
MD or Steepest Descent?
Not minimize a structure
without the ligand in, as the
binding site might just
collapse
Minimize with steepest
descent algorithm, not with
MD protocols that could
make your atoms move away
if protein have a small bump
in your starting structure
Protein Preparation
Key steps/factors!
Check alternate (“alt”) locations
or multiple conformations AA
Protonation, Tautomerism,
Orientations - add H & optimise
Check AA flipping & H direction
Define cofactors, ligands, metal
ions, waters
Define sites understanding
motifs, catalytic sites, key AA
Good protocol and can be
confident in your results

6. Views & Opinions
Couldn’t get into an
academic institution (of ur choice) to teach?
Try teaching everyone online!
Understand the existing knowledge
Tutorials are just ‘How to do’ but not about the
‘What to take care?’ - Users should take care!
Good synergetics between human expertise &
computational tools
Avoid Missed Opportunities
Understand significance of
parameters/properties
Evaluate and decide the tool/approach
Check reliability of data used

7. Thanks!
@giribio
Forum Discussion & Contributors
Mentors, Students and Feedbacks
Next topic:
3D QSAR?
How to choose PDB for Docking?