Six Easier Pieces*:
Discovering the 3D structure of Substance P,
using only free internet tools.

L. Van Warren
University of Arkansas for Medical Sciences
Department of Anatomy - College of Medicine
& Arkansas Center for Cancer Research

June 12, 1999


Living systems favor the use of small molecules as tokens of exchange in a complex self-sustaining biochemical economy. Examples are oxygen, and carbon dioxide in respiration, the alkali metals in serum electrolytes, glucose in energy storage and a host of others. There are several neurotransmitters that are essential for nerve signal transmission in biological organisms. Most of these are also relatively small molecules. Among them are histamine, dopamine, and serotonin. Others, such as bradykinin and Substance P are molecular bills of slightly larger denomination , the later consisting of 11 amino acids linked by 10 peptide bonds. The structure of the common neurotransmitters have been published on the world wide web, the exception being the subject of this short note, the tachykinin called Substance P.

Neurotransmitters Of Pain
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Structure Table ©1999 L. Van Warren

Histamine Sites
dopamine drawing
Histamine Properties

Dopamine Sites
dopamine drawing
Dopamine Properties

Serotonin Sites
serotonin drawing
Serotonin Properties

Bradykinin Sites
bradykinin drawing
Bradykinin Properties

Substance P Sites
Substance P Properties


The official definition of tachykinins from the NCBI database is:


Further investigation reveals that the term Substance P is an alias for several analogs, whose amino acid sequence varies with species. Some of these are given in the following table:

Table 1: Substance P analogs by species

same as above
same as above
same as above


At this writing a thorough search of the web does not yield the three dimensional configuration of Substance P. The "P" in substance P actually stands for powder. When isolated for the first time from horse intestine in the 1930s, it was in powder form.

The point of this technical note is twofold, first the completion of an errand to determine the 3D structure of substance P for a cancer research project, and secondly, to show how it is relatively easy to apply this procedure to other molecules of interest.

Six Easy Steps: Deducing 3D biochemical structures via the web:

Step 1: the amino acid sequence is obtained via NCBI Entrez, it is: KPRPGQFFGL M as seen in the table above.

Step 2: using an/ or the simpler quick aa table one can find that this 11 symbol string translates to:

Step 3: the L-forms of all the amino acids are pasted into the freely distributed ChemDraw Net product left to right, top to bottom as shown in the figure below:

Step 4: the peptide bonds are formed by condensing out a water using a hydrogen from the primary amine groups and a hydroxyl group from the carboxyl groups:

These peptide bonds are formed by when the line is connected. A hydrogen disappears automatically, but the hydoxyl groups, such as the one seen remaining on the proline in the first row, are erased manually after assembly.

Step 5: In the freeChemDraw Net 4.5 tool there is an option called clean-up structure. Clicking on it produces a more aesthetic 2-D drawing of the structure:

This feature is not in the ChemDraw Standard ($299 academic version), but it is in the ChemDraw Pro version (also $299 at this writing Cambridge software runs specials from time to time, but they can do their own advertising!). If you install ChemDraw Standard, it will ask you if you to delete your ChemDraw Net 4.5, which causes structure clean-up to stop working.

Step 6: In the final step, we select the entire structure in ChemDraw using either the square or round marquee lasso tools. We then choose the option Copy As from the Edit menu and which results in a text representation of the structure being transferred to the system clipboard in SMILES format. Pasting the clipboard contents into another application results in this SMILES text string, representing the structure of Substance P, being transferred. This SMILES text string looks like:


When this text string is emailed to the Corina Web Service in Germany, the result is the three dimensional structure below:


The SMILES string for substance P turns out to be 12 characters too long for the interactive 3D service, otherwise we could have obtained the structure in almost real time. The overnight service via email instructions is utilized instead.


Althought the resulting conformation is useful for appreciating three dimensional molecular structure, it is non-unique and often unrealisitic. It is necessary to perform energy minimization to predict plausible configurations of the molecule. This was done using the CS Chem3D Pro software, which was also available free of charge through a special CS web promotion:

The conformation of the final molecule is much different from that of the original. The reader is urged to enumerate the number of plausible conformations as a combinatorial exercise.


This simple six step process can be applied to a large variety of biochemistry applications. The author intends to continue refining this approach for the illustration of biochemical pathways. The enthusiastic reader is urged to repeat these steps for the other analogs listed in table 1.


*Apologies to the late great Richard Feynman for the title. His book by the same name is wonderful and the title is a tribute. The tools ChemDraw 3D and the Corina 3D structure service have made this otherwise tedious and difficult task nearly effortless. A debt of gratitude is owed by the biochemistry community to them for the fine capabilities they are providing. Thanks to Don DeLuca of UAMS and Steven Fleisler of St. Louis University for clarifying the condensation conventions for peptide bonds. Thanks to MDL for developing the Chime plug-in for 3D viewing in Netscape and Explorer. Thanks to Eric Martz for clarifying Chime installation procedures on the server side. Appreciation to Dr. Reed Thompson of UAMS/ACRC for sponsoring related work on cancer pain, which gave rise to this neurotransmitter investigation. A sincere note of gratitude is due to Dr. Wolf-D. Ihlenfeldt Computer Chemistry Center, University of Erlangen-Nuernberg Erlangen (Germany) who has developed an interactive structure service. Appreciation to Marilyn Fulper-Smith for review and assistance. A special thanks also to Mark Turpin whose web sponsorship and innovation, none of this would have been possible. Emily Lowry, a high school intern at UCSF, provided the lexical history of substance P.