User Guide for LeWater

User Guide for LeWater
Email: [email protected]
Website: www.lephar.com
Copyright 2013 © Lephar Research. All rights reserved.
1. Hydrogen bonding penalty
Hydrogen bonds are very important for binding specificity, but can be made by the
ligand either in the protein or in solution. In order to form hydrogen bonds between
the ligand and the protein, donors and acceptors firstly have to break hydrogen bonds
with water, and then form new hydrogen bonds. In this sense, the enthalpic gain by
formation of new hydrogen bonds is marginal and the gain is mainly entropic due to
releasing waters into bulk. However, if newly formed hydrogen bonds between the
ligand and the protein are not in good geometry or desolvated donors/acceptors are
not involved into new hydrogen bonds, an enthalpic loss arises due to uncompensated
breakage of hydrogen bonds with waters.
The program is developed to calculate the hydrogen bonding penalty index in the
nature of enthalpy by checking both the solvation and hydrogen bonding state of
donors/acceptors at the protein-ligand interface. Further integrating the hydrogen
bonding penalty into a scoring function, it is found that a value of 1 in penalty
corresponds to about 1.7 kcal/mol in binding free energy, which is in good agreement
with the experimental value, e.g., breakage of a neutral hydrogen bond resulting in
loss of energy from 0.5 to 1.5 kcal/mol.
The program can also be used to generate a water map at the protein-ligand
interface to facilitate hit-to-lead optimization.
2. Usage
$LeWater
Get “Help” information.
$LeWater [input file] [protein PDB file] [ligand list]
Calculate the hydrogen bonding penalty and fitness of hydrogen bonds specified at
the protein-ligand interface.
$LeWater [input file] [protein PDB file] [ligand list] -omap
Generate a water map at the protein-ligand interface.
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3. Input
3.1. Protein PDB coordinate file
Explicit hydrogen atoms should be included in the PDB file.
3.2. Ligand list
A list specifies the path of the ligands in PDB format such as
//
L01.pdb
L02.pdb
L03.pdb
……
3.3. Input file
In the input file, define the protein-ligand interface and specify donors/acceptors of
the protein together with hydrogen bonding weight according to the specific atom
type/environment. An example is as follows:
//
Pocket
Xmin
Xmax
Ymin
Ymax
A186
NH2
HH21
0
B99
OH
HH
Zmin
Zmax
Donor
….
Acceptor
157
OD1
158
O
69
OH
0
0.5
….
END
[Pocket]
Defines the size of the protein-ligand interface in a cubic box. It should be about 6 Å
further away from the docked ligand. Recommended size: 6 Å further away from the
binding site defined for docking. Too big an interface will increase the computational
time.
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[Donor]
A186
NH2
HH21
0
A: Chain Identifier. For more than one chain in the protein structure like HIV protease,
please specify the chain identifier. If just one chain, the chain identifier can be omitted.
186: Residue number
NH2: donor heavy atom
HH21: donor hydrogen
0: weight for this atom type. Default weight: 0.5 if left blank.
[Acceptor]
157
OD1
0
157: Residue number. If more than one chain, please specify the chain identifier.
OD1: Acceptor
0: weight for this atom type. Default weight: 1 if left blank. For oxygen in a hydroxyl
group of the side chain of Tyr/Ser/Thr, the recommended weight is 0.5, which need to
be set manually.
69
OH
0.5
4. Output
The result is saved in a file named “filter”.
L01.pdb
0.8
P: 0.3
L: 0.5
Dpro: 1.0 0.2 0.0 Apro: 1.0 0.5 0.0
The first number is the overall hydrogen bonding penalty, the second is the penalty
from the protein and the third is from the ligand. The following number indicates the
fitness of hydrogen bonds formed with the specified donors/acceptors in the input file,
with 0 indicates no hydrogen bond and 1 means a perfect hydrogen bond.
The water map is saved in a file “omap.pdb”.
5. Important Notes
1) In the input file, one has to specify all potential donors/acceptors at the proteinligand interface that could form hydrogen bonds with the potential ligand.
Otherwise, missing donors/acceptors could lead to artificial hydrogen bonding
penalty.
2) Default weight for donor: 0.5. Side chains of residues such as Lys/Arg on the
protein surface are rather flexible. Considering flexibility (which should be judged
based on the structure), the weights for such hydrogen bonding donors could be set
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to 0. So that those atoms have no penalty even they are desolvated by hydrophobic
groups of the ligand, and function only as potential donors/acceptors for ligands
3) Default weight for acceptor: 1. However, Acceptor may have different weights
depending on the specific atom type (e.g., 0.5 for hydroxyl oxygen). If the weight
by the atom type is not 1, it should be set explicitly. Oxygen typically can accept
two donors, if it has already been involved into a hydrogen bond, the
recommended value is 0 (even the weight is 0, please do add it in the input file as
it still could function as an acceptor to form a hydrogen bond with the potential
ligand. A small weight of e.g., 0.1 can also be used).
4) The weights can be tuned by the users according to the specific requirement.
Reference
1. Hongtao Zhao, Danzhi Huang; Hydrogen bonding penalty upon ligand binding.
PLoS One, 6, e19923 (2011).
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