Converting SMILES string and 2D ChemDraw structures into 3D molecular structures

Software required for this tutorial

• Bash terminal: Main language used to run code

  • On Mac: Command + space, type in "Terminal" and hit enter

  • On Windows 10:

    • Install gitbash: https://gitforwindows.org/

    • Alternatively, use the ubuntu add-on: https://www.omgubuntu.co.uk/2016/08/enable-bash-windows-10-anniversary-update

• Openbabel Version 2.4.1 [Link]: Main workhorse for converting representations

  • On Mac:

    • Open terminal and run: brew install open-babel

  • On Linux:

    • Download bash installation file [Link]

    • Store in the server, then run: bash babel_install_code.sh

    • After running the code, make sure to add 'export PATH="${HOME}/local_install/openbabel-2.4.1/bin:$PATH"' into your ~/.bashrc

    • Restart terminal for .bashrc commands to take into effect

• ChemDraw [Link]: Used for drawing 2D structures

• Avogadro [Link]: Used for visualizing 3D structures

Files for this tutorial:

All input/output files are downloadable through GitLab [Link].

This folder contains the following:

• images: Directory containing all images for this tutorial

• output_files: Output files from this tutorial (e.g. converted .mol2 structures)

• example_structure.cdx: ChemDraw example used in this tutorial

Part 1: Generating 2D chemical structures and SMILES strings

Part 2: Converting SMILES or ChemDraw structure to 3D geometries

2.0. ChemDraw to 3D geometry

Step 2.0.0: Open terminal with openbabel installed and go into the directory where your *.cdx is stored.

Step 2.0.1: Run obabel and convert into mol2 file:

obabel -icdx example_structure.cdx -omol2 -h > example_structure.mol2

• "-icdx" means the input is a *.cdx file

• "-omol2" means to output a *.mol2 file

• "-h" means to add hydrogens if missing

• "> example_structure.mol2" means to redirect output to .mol2 file.

• Side note: I tried ".cdxml" as an input ChemDraw, but it does not correctly convert to .mol2 files.

Step 2.0.2: The .mol2 file is not energy minimized, so run the following to minimize structure

obminimize -sd -ff MMFF94s -c 1e-6 -n 50000 -o "mol2" example_structure.mol2 > example_structure_minimized.mol2

• "-sd" means to energy minimize with steepest descent

• "-ff MMFF94s" means to run the MMFF94s force field

• "-c 1e-6" means to run minimization until tolerance of 1e-6 difference is reached, OR

• "-n 50000" means 50,000 minimization steps have been performed

• "> example_structure_minimized.mol2" means to redirect output to a mol2 file

Now, you should have successfully converted a ChemDraw structure into a 3D structure!

Alternative one step command (using gen3d):

obabel -icdx example_structure.cdx -omol2 -h --gen3d > example_structure_gen3d.mol2

• "--gen3d" means to search for 3d conformers

The alternative method produces similar results to obminimize. For simplicity, you could use gen3d for a quick transformation. Feel free to use Avogadro to visualize the different structures and compare them.

2.1. SMILES to 3D geometry

Step 2.1.0: Open terminal with openbabel installed.

Step 2.1.1: Run the following command to generate the *.mol2 file

obabel -:"SCCCCCCCCCCCO" -omol2 -h --gen3d > smiles2mol_example_smiles_1.mol2

• "-:" means the input is a SMILES string

• "-h" means to add hydrogens if missing

• "--gen3d" means to search for 3d conformers (see link: https://open-babel.readthedocs.io/en/latest/3DStructureGen/Overview.html)

Alternatively, if you have the SMILES in a file

echo "SCCCCCCCCCCCO" > smiles2mol_example_smiles_2.smi

obabel -ismi smiles2mol_example_smiles_2.smi -omol2 -h --gen3d > smiles2mol_example_smiles_2.mol2

• "echo..." creates a file with the SMILES as the first line

• "obabel..." converts the smiles string to a mol2 file with a "-ismi" flag to input the smiles file

Congrats! You should now be able to convert SMILES strings to 3D geometries!

Optional Step: Generating script to for-loop through many structures

Given that Openbabel could quickly change in-between molecules , one could imagine that you could input a large library of ChemDraw files (*.cdx) or SMILES strings. The Bash script below loops through all *.cdx files and converts them to 3D structures (*.mol2 files).

Code to convert *.cdx files to *.mol2 files in a for-loop fashion:

#!/bin/bash

# openbabel_convert_cdx_to_mol2.sh

# This function converts chemdraw structures to mol2 files.

# It will search for all possible *.cdx file, then run open babel to convert them to mol2

# It will also run energy minimization

#

# Written by: Alex K. Chew (04/16/2020)

# INPUT VARIABLES

# $1: input raw directory folder

## DEFINING MAIN DIRECTORY TO WORK ON

current_raw_dir="${1-${MDLIG_RAW_DIR}}"

#######################################

### DEFAULT VARIABLES FOR OPENBABEL ###

#######################################

## FORCE FIELD

em_forcefield="MMFF94s"

## TOLERENCE

tolerence="1e-6"

## DEFINING MAX NUMBER OF STEPS

max_steps="50000"

## FINDING ALL CDX FILES

read -a cdx_files <<< $(ls ${current_raw_dir}/*.cdx )

## CREATING TRASH

path_trash="${current_raw_dir}/openbabel_initial_structures"

## PRINTING

echo "---- CDX FILES ----"

for each_cdx in ${cdx_files[@]}; do

echo "=== ${each_cdx} ==="

## GETTING BASENAME

cdx_basename=$(basename ${each_cdx})

## GETTING THE FILE PREFIX

file_prefix="${cdx_basename%.cdx}"

## FINDING MOL2

mol2_file="${file_prefix}.mol2"

path_mol2="${current_raw_dir}/${mol2_file}"

## CHECKING IF EXISTING

if [ ! -e "${path_mol2}" ]; then

## CREATING TRASH DIRECTORY

if [ ! -e "${path_trash}" ]; then

mkdir -p "${path_trash}"

fi

echo "Performing mol2 conversion with openbabel"

## DEFINING TEMP FILE

temp_mol2_file="${file_prefix}_initial.mol2"

## CONVERTING CDX TO MOL2 AND ADD HYDROGENS

obabel -icdx "${each_cdx}" -O "${path_trash}/${temp_mol2_file}" -h

## PERFORMING ENERGY MINIMIZATION

obminimize -sd -ff "${em_forcefield}" \

-c "${tolerence}" \

-n "${max_steps}" \

-o "mol2" \

"${path_trash}/${temp_mol2_file}" > "${path_mol2}"

## PRINTING

echo "Openbabel conversion is complete!"

else

echo "${path_mol2} exists!"

fi

done

To run, simply copy the code into a script "openbabel_convert_cdx_to_mol2.sh" and run:

bash openbabel_convert_cdx_to_mol2.sh PATH_WITH_CDX_FILE

Replace "PATH_WITH_CDX_FILE" with the path to a folder with *.cdx files