Subject: Summary: Cavities in Proteins

From: Qu Chunxu <[email-masked]>
Date: Fri, 24 Nov 95 17:34:00 JST

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Dear netter,
Several days ago I posted a question at this list, and I got some methods to
solve my problem. Here I want to express my sincerest thanks to all of you
who pay attention to my problem. The following is the summary of the answers
I received:

PROBLEM:

>Dear netters,
>
>I met a problem on cavity volume calculation.
>
>I am studying on the thermostability of 3-isopropylmalate dehydrogenase.
>Protein engineering showed that at a certain site, Ala-->Leu mutation
>increased the stability of protein. Crystallography analysis showed that the
>sidechain of Leucine reduced the cavity around mutation site. Although the
>dot surface illustration can show this point very well, we are asked to give
>the cavity volume in each case. However, we have no such a program. Could you
>help me? Thanks in advance.

ANSWERS:
1) summary from [email-masked]

I asked a more generally question concerning cavities
in this forum - I am using "GRASP" to find the cavities and
give the area or volume of these cavities.

If the program does not find  a cavity around the mutation site. then
I am not sure how you could quantify (volum/area) it.

Anyway: here are the answers to my question:

===================================
From: [email-masked] (Volkhard Helms)
Date: Tue, 31 Oct 1995 12:25:14 +0100

Hello,

the 'standard' way is to role a solvent probe over the protein surface.
Different probe radius are being used (1.25A - 1.4A).

The GRASP program has a very easy to use implementation that spits out the
volume of the cavities and displays a molecular surface of the cavities.

You might be interested in the following two papers:
Williams et al. Protein science, 3, 1224-1235 (1994) and
Hubbard et al. Protein engineering, 7, 613-626 (1994)
that deal with protein cavities.

Hope this helps,

Volkhard
--
Volkhard Helms
European Molecular Biology Laboratory
Meyerhofstr.1
69012 Heidelberg, Germany
Tel. +49 - 6221 - 387255
e-mail: [email-masked]

================================================
From: Leif Laaksonen <[email-masked]>
Subject: Re: CCL:Cavities within proteins

Hi,

You should be able to calculate them in much the same way as we did it
for cavities in polyisobutylene (PIB):

http://www.csc.fi/lul/chem/movies/pib/pib_movies.html

Regards,

-leif laaksonen
-------------------------------------------------------------------
Leif Laaksonen                     |
Center for Scientific Computing    | Phone:      358 0 4572378
P.O. Box 405                       | Mobile:     358 400425203
FIN-02101 Espoo                    | Telefax:    358 0 4572302
FINLAND                            | Mail:  [email-masked]
---------URL: http://laaksonen.csc.fi/leif.laaksonen.html----------

======================================
From: [email-masked]
Subject: Finding and filling protein cavities. J Mol Graph

Is this what you're looking for?  [Sometimes I'm way off on interpreting the
question.]
----------------------------------------------------------------
1
AU  - Delaney JS
TI  - Finding and filling protein cavities using cellular logic
      operations
MH  - Proteins
MH  - Methods
MH  - docking
MH  - Protein Binding
MH  - Binding Sites
MH  - Cytochrome P 450
MH  - Logic
MH  - Models,Molecular
MH  - Pattern Recognition
MH  - Protein Conformation
MH  - Software
AB  - A method for solid-filling protein cavities is presented. The
      method uses a pattern-recognition technique based on cellular
      logic operations to distinguish between convex and concave
      regions of a protein. In doing this it solid fills protein
      cavities and automatically defines a boundary between cavity and
      exterior free space. The operations used to fill the cavities
      also can be used to process the filler to filter out small-scale
      features. So far the main use of the method has been in
-->   visualizing protein active sites for docking. The method can be
-->   used to find cavities of a given size range and could be used to
      find novel protein binding sites
SO  - J Mol Graph  1992;10:174-7

Ed
---------------------------------------------------------------------------
Edward C. Hauer                                         /\
Dept Cell Biol Biochem                          GOOD  /    \  FAST
Toxinology Division, USAMRIID                       /        \
Ft. Detrick, MD  21602-5011 USA                   /  Pick Two  \
301 619-4813  619-2348 fax                      /________________\
[email-masked]                        CHEAP

====================================================================
From: gareth <[email-masked]>
Subject: Re: CCL:Cavities within proteins

Have a look at:

Cavity search: an algotithm for the isolation and display of
cavity-like binding regions.
Ho & Marshall JCAMD 4 (1990) 337-354

and

Finding and filling protein cavities using cellular logic operations.
Delaney JMolGraph 10 (1992) 174-177

Gareth.

--
Gareth Jones

Dept of Information Studies and Krebs Institute for Biomolecular
Research
University of Sheffield, UK

E-mail   [email-masked]

==================================================================

From: [email-masked] (Dr. Chris L. Waller)
Subject: Re: CCL:Cavities within proteins
Status: R

Chris M.W. Ho and Garland R. Marshall have a program named appropriately
CAVITY. Contact Center for Molecular Design, Washington University, St.
Louis, MO.

%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%
 Chris L. Waller, Ph.D.
 Modeling Team Leader / Research Chemist
 Pharmacokinetics Branch (MD-74)
 Experimental Toxicology Division
 National Health and Environmental Effects Research Laboratory
 U.S. Environmental Protection Agency
 Research Triangle Park, NC 27711
 (919) 541-7976 (office)
 (919) 541-0704 (lab)
 (919) 541-5394 (fax)
 [email-masked]
%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%

==========================================================================

From: Vincent Collura <[email-masked]>
Subject: Re: CCL:Cavities within proteins

There is an article in Protein Engineering (1994 or 1995) from Patrick Argos et
al.

Cheers Vincent.

=========================================================================
From: Roman Laskowski <[email-masked]>
Subject: Cavities in proteins

Dear Eldbjoerg,

A colleague of mine here at University College London has passed me your
enquiry about calculating cavities in proteins.

I have a program called SURFNET which does just that. The paper describing
it should appear in the next issue of J.Mol.Graphics, but you can find out
about the program, and how to get a copy, via the following URL:

http://www.biochem.ucl.ac.uk/~roman/surfnet/surfnet.html

Cavities and surface clefts are computed as "gap regions" between atoms of
the protein. Alternatively, you can compute gaps between two molecules,
such as the separate chains of a dimer, or the gaps between a protein and
its ligand. The program's output can be viewed on a number of molecular
modelling packages used for displaying proteins, such as Quanta, O, Sybyl
and Insight.

The source code (in FORTRAN) is free to academic users. All you need to
do is sign and return a Confidentiality Agreement.

There are several other programs that compute cavities. Below I give the
LaTeX version of an extract from my SURFNET paper mentioning the other
programs and giving references.

I hope this helps.

Best wishes,

Roman Laskowski.

------------------------------------------------------------------------

A number of programs are available for visualizing molecular surfaces and
cavities. Molecular surfaces are most usually displayed as
dot-surfaces$^{\cite{Connolly 1983}}$ by the commonly-used molecular
modelling programs, such as {\em O}$^{\cite{Jones et al 1991}}$ and {\sc
quanta}$^{TM}$ (Molecular Simulations Inc., Burlington, MA, USA). The dots
are placed at the van der Waals radius of each atom, at a given density and
colouring, and provide an indication of the molecular surface.  Where two
molecules interact, their dot-surfaces can show their complementarity at
the interface.

Solid renderings of surfaces can also be generated by these and other
packages (ref. \cite{Zauhar 1995} and references therein), with appropriate
texturing and reflections$^{\cite{Connolly 1993}}$. For large molecules,
such as proteins, these representations are difficult to manipulate
interactively on the graphics, although graphics packages exist that can do
this well, such as {\sc avs} (Advanced Visual Systems Inc., Waltham, MA,
USA). One excellent program designed specifically for visualizing molecular
surfaces, and in particular their electrostatic potentials, is {\sc
grasp}$^{\cite{Nicholls et al 1993}}$ which has quickly become very popular
because of the striking images it generates.

Various methods and programs exist for visualizing cavities and surface
grooves. Both types of region are difficult to perceive from just viewing a
molecular surface alone. A given cavity, as defined by the convex surface
of the atoms surrounding it, is a concave region which, because the atoms
cannot fit together without leaving gaps, branches into myriads of channels
and grooves in all directions and is impossible for the mind to
grasp. Programs that best depict cavities, therefore, show them as convex
surfaces, often built up by fitting probe spheres into the cavities in some
manner, and then defining a surface around the resultant collection of
inter-penetrating spheres. By defining a minimum sphere size, the myriads
of small gaps and crevices between the atoms are excluded and only the
significant gaps are depicted.

Internal cavities, which are completely closed off from the outside world,
are relatively easy to detect. The program of Ho \& Marshall$^{\cite{Ho &
Marshall 1990}}$, for example, `flood-fills' a cavity from a given start
point. The {\sc voidoo} program$^{\cite{Kleywegt & Jones 1994}}$ detects
cavities, and certain invaginations as well, by an `atom-fattening'
procedure which progressively closes off small channels both between
cavities and also between cavities and the outside world by gradually
increasing the atomic radii. The {\sc hole} program of Smart {\em et
al.}$^{\cite{Smart et al 1993}}$ is specifically geared to identifying,
measuring and visualizing ion channels in proteins, stepping through the
channel from a given start-point and filling it with spheres.

Some programs locate internal cavities as a by-product of generating the
molecular surface. For example, the {\sc grasp} program, mentioned above,
locates internal cavities on the basis of the connectivities of the surface
elements. Similarly, the algorithm of Voorintholt {\em et
al.}$^{\cite{Voorintholt et al 1989}}$, which is used by the {\sc what if}
molecular modelling package$^{\cite{Vriend 1990}}$, can show the molecular
surface that is accessible to different probe sizes as a density map, and
so can detect the molecule's internal cavities.

Surface grooves and indentations, on the other hand, are much more
difficult to depict - principally because of the difficulty of knowing how
far into open space to extend the groove region; where does the `sea level'
of that part of the surface lie?  The program of Delaney$^{\cite{Delaney
1992}}$ uses a pattern recognition technique to identify the limits for the
flood-filling procedure. The {\sc pocket} program$^{\cite{Levitt & Banaszak
1992}}$ is an interactive cavity-filling program which detects pocket
regions in the structure by placing trial a sphere of a given radius at
points on a 3D grid. At each grid-point the sphere either makes, or does
not make, contact with atoms from the molecule. Regions of no contact which
are bounded by contact regions in either the $x$-, $y$- or $z$- directions
are deemed to be cavities or pockets.

Other cavity-detection algorithms concern themselves primarily with the
detection and analysis of cavities rather than with their visualization
(for example, refs \cite{Hubbard et al 1994}--\cite{Williams et al
1994}). These usually involve moving a probe sphere about the surface to
detect completely or partially buried voids.

References:-
----------

\bibitem{Connolly 1983} Connolly, M. L. Analytical molecular
surface calculation. {\em J. Appl. Cryst.} 1983, {\bf 16}, 548--558

\bibitem{Jones et al 1991} Jones, T. A., Zou, J-Y., Cowan, S. W., and
Kjeldgaard, M. Improved methods for building protein models in electron
density maps and the location of errors in these models. {\em Acta Cryst.}
1991, {\bf A47}, 110--119

\bibitem{Zauhar 1995} Zauhar, R. J. SMART: a solvent-accessible
triangulated surface generator for molecular graphics and boundary element
applications. {\em J. Comput. Aided Mol. Des.} 1995, {\bf 9}, 149--159

\bibitem{Connolly 1993} Connolly, M. L. The molecular surface
package.  {\em J. Mol. Graph.} 1993, {\bf 11}, 139--141

\bibitem{Nicholls et al 1993} Nicholls, A., Bharadwaj, R., and Honig,
B. GRASP: graphical representation and analysis of
surface-properties. {\em Biophys. J.} 1993, {\bf 64}, A166

\bibitem{Ho & Marshall 1990} Ho, C. M. W., and Marshall, G. R. Cavity
search: an algorithm for the isolation and display of cavity-like binding
regions. {\em J. Comput. Aided Mol. Des.} 1990, {\bf 4}, 337--354

\bibitem{Kleywegt & Jones 1994} Kleywegt, G. J., and Jones,
T. A. Detection, delineation, measurement and display of cavities in
macromolecular structures. {\em Acta Cryst.} 1994, {\bf D50}, 178--185

\bibitem{Smart et al 1993} Smart, O. S., Goodfellow, J. M., and Wallace,
B. A. The pore dimensions of gramicidin A. {\em Biophys. J.} 1993, {\bf
65}, 2455--2460

\bibitem{Voorintholt et al 1989} Voorintholt, R., Kosters, M. T., Vegter, G.,
Vriend, G., and Hol, W. G. J. A very fast program for visualizing protein
surfaces, channels and cavities. {\em J. Mol. Graphics} 1989, {\bf 7},
243--245

\bibitem{Vriend 1990} Vriend, G. WHAT IF: a molecular modeling
and drug design program. {\em J. Mol. Graphics} 1990, {\bf 8}, 52--56

\bibitem{Delaney 1992} Delaney, J. S. Finding and filling
protein cavities using cellular logic operations. {\em J. Mol. Graph.}
1992, {\bf 10}, 174--177

\bibitem{Levitt & Banaszak 1992} Levitt, D. G., and Banaszak, L. J. {\sc
pocket}: a computer graphics method for identifying and
displaying protein cavities and their surrounding amino acids. {\em
J. Mol. Graphics} 1992, {\bf 10}, 229--234

\bibitem{Rashin et al 1986} Rashin, A. A., Iofin, M., and Honig, B. Internal
cavities and buried waters in globular proteins. {\em Biochemistry} 1986,
{\bf 25}, 3619--3625

\bibitem{Alard & Wodak 1991} Alard, P., and Wodak, S. Detection of
cavities in a set of interpenetrating spheres. {\em J. Comp. Chem.} 1991,
{\bf 12}, 918--922

\bibitem{Williams et al 1994} Williams, M. A., Goodfellow, J. M., and
Thornton, J. M. Buried waters and internal cavities in monomeric
proteins. {\em Protein Sci.} 1994, {\bf 3}, 1224--1235

========================================================================

From: David Clark <[email-masked]>
Subject: CCL: cavities in Proteins

Hello,

Here is a reference that might be of interest:

author = "Lewis, R.A. ",
title  = "Determination of Clefts in Receptor Structures ",
journal = "Journal of Computer--Aided Molecular Design ",
year = "1989 ",
volume = "3 ",
pages = "133--147 ",

There was also a paper by Ho and Marshall back in 1992 or 1993 about
a program called CavitySearch - it was in JCAMD, I think.

Best wishes

David Clark
.,

David E. Clark                   |
Proteus Molecular Design Ltd.,   |  Tel: 01625-500555
Lyme Green Business Park,        |  Fax: 01625-500666
Macclesfield, Cheshire,          |  Email: [email-masked]
SK11 0JL, UK                     |

===================================================================

From: [email-masked] (Pieter Stouten)
Subject: Re: CCL:Cavities within proteins

Check out WHATIF by Gert Vriend <[email-masked]>.

Cheers, Pieter.

** Note that my e-mail address has changed once again. I hope it will not **
** happen again soon. Please use [email-masked] from now on.    **

Pieter Stouten                              ||  Nothing shocks me;
Computer Aided Drug Design Group            ||
The DuPont Merck Pharmaceutical Company     ||  I am a scientist!
P.O. Box 80500, Wilmington, DE 19880-0500   ||
Phone: +1 (302) 695 3515                    ||          --
Fax: +1 (302) 695 2813                      ||
Internet: [email-masked]          ||    Indiana Jones

========================================================================

From: Craig Taverner <[email-masked]>
Subject: Re: CCL:Cavities within proteins

What do you mean by "calculate cavities"?
Do you mean calculate the cavity volume?
If so, I have a program I wrote to calculate the volume of cavities in
crystals, but should work for proteins too if you already know where the
cavity is.
If you're interested the program is:
ftp://hobbes.gh.wits.ac.za/pub/steric/steric_1.08.tgz
It's original purpose was for cone and solid angle calculations, but it
has since been substantially extended.

Cheers, Craig

"If God had meant us to be naked, we would have been born that way."

Craig Taverner
Structural Chemistry, University of the Witwatersrand, South Africa

===================================================================

From: Scott Weston <[email-masked]>
Subject: Re: CCL:Cavities within proteins

Eldbjoerg,

Depending on what your exact needs are, one good approach to the
isolation and visualization of protein cavities is the one encoded
in the CAVITY SEARCH program by Chris Ho and Garland Marshall at
the Center for Molecular Design (J Comput Aided Mol Des (JCB), 1990
Dec; 4 (4): 337-54.  More information is available at their Web site
at http://wucmd.wustl.edu.

Good luck,

Scott

Scott Weston                   Lab Phone:  (601) 232-7187
Grad. Student                  Lab FAX:  (601) 232-5118
Dept. of Medicinal Chemistry   Home Phone:  (601) 234-0067
University of Mississippi      [email-masked]
University, MS  38677								
=================================================================

From: [email-masked] (Marvin Waldman)
Subject: Finding cavities in proteins

Hi Eldbjoerg,

A nice algorithm for doing this can be found in the following reference:

"Finding and filling protein cavities using cellular logic operations,"
John S. Delaney, J. Mol. Graphics, vol. 10, pp. 174-177 (1992).

Regards,

Marvin Waldman, Ph.D.
Biosym/MSI
e-mail: [email-masked]

=========================================================================

From: john delaney <[email-masked]>
Subject: re: cavities in proteins

Dear Eldbjorg,

With regards to your query, I published a paper on the subject 3 years ago in
the Journal of Molecular Graphics. Briefly, the program described finds
cavities in proteins using a simple pattern recognition technique. The paper
includes some references to similar work by other people.

John S. Delaney, Finding and filling protein cavities using cellular logic
operations, J. Mol. Graphics, 1992, Vol 10, pp 174-177

I can send a reprint if your interested. Hope this helps.

John Delaney

Zeneca Agrochemicals,
Jealott's Hill Research Station,
Bracknell,
Berkshire,
UK

E-mail: [email-masked]

===============================================================

From: "Don Gregory" <[email-masked]>
Subject: CCL:Protein Cavities

Quanta/Protein users will recognize this as a capability in
the Protein Health toolset.

Don Gregory

=================================================================

From: [email-masked] (Michael L. Connolly)

I've written some C software for identifying protein cavities.
I license source code to universities for what I think is a modest fee.
$300 (U.S.) for PQMS, which computes volumes & areas;
$200 (U.S.) more for TRB, which converts PQMS output to SGI Inventor files
Please take a look at my anonymous ftp site:

ftp.netcom.com

cd pub/co/connolly

In particular, fetch my documentation in RTF format:
cavity.rtf
and sample output files in SGI Inventor and Image formats:
lysozyme.iv
lysozyme.rgb

Please send me E-mail if you have any questions.

Mike
 Michael L. Connolly			[email-masked]
 1259 El Camino Real, #184		(415) 780-0321 (voice)
 Menlo Park, CA  94025			(415) 780-0321 (fax)
 United States of America		(415) 326-4203 (fax)

-------------------------------------------------------------------

2) Program MSDOT(Connolly)    from [email-masked]
  Just have a look at the QCPE bulletins. There are some programs like GEPOL,
  MSDOT (Conolly), one by Richards and some programs, which inhibit some of the
  secodes in one.

				   Bye, AHG...

    Andreas Goeller               Computer Chemie Centrum der
    Dipl.-Chem.                  Universitaet Erlangen/Nuernberg
				       Naegelsbachstr. 25
 phone: +49(0)9131-856583               D-91052 Erlangen
 fax: +49(0)9131-856565                   Germany
 email: [email-masked]
 http://www.organik.uni-erlangen.de
-----------------------------------------------------------------

3) QUANTA/PROTEIN HEALTH/HOLES
*	from [email-masked]

My colleague told me that the software QUANTA 4.0 from Molecular Simulations,
Inc. (MSI) has a module for cavity volume calculations.  You can call MSI at
(03)3818-6511 in Japan.

Sincerely,

Masayuki Yuki
University of Southern California
School of Pharmacy
[email-masked]

-------------------------------------------------------------------

**	from [email-masked] (Mark J Forster )
The Quanta/Protein Health software includes a tool for locating holes
in a protein structure that are typically large enough to accomodate a
water molecule. The method places the protein on a 3D grid and tags grid points
as either protein or solvent depending upon their proximity to a protein atom.>
Once the grid points for bulk solvent around the protein are identified by
a flood fill technique then the non protein grid points that remain are
possible solvent sized cavities within the protein. The minimum size of the
hole detected may be set by the user.

Hope this helps.

Best Wishes       __________________________________________________________
Mark             /
         ___    /
	/  /|  /                     Mark J Forster
       /  / | /                     Biosym / Molecular Simulations.
      /__/__|/     \__O_/          9685 Scranton Rd,
     /__/             |           San Diego, CA 92121, USA.
    /   |            /|          Tel: (619) 458 9990
   /  o |<--------  / |         FAX: (619) 458 0136
  /__ __|                      e-mail: [email-masked]

-------------------------------------------------------------

4) ftp://hobbes.gh.wits.ac.za/pub/steric/steric_1.08.tgz
  from [email-masked]

I have a program to calculate various steric effects in molecules and
crystals, and recently added a cavity volume calculation to it for the
calculation of the cavity volume in the region of perchlorate groups in
crystals.  The main way of calculating the cavity volume is using a Monte
Carlo sampling approach, which gives very fast results, with moderate
accuracy.  There are four different cavity volumes calculated, depending
on exactly what is meant by cavity volume (depends mainly on how you
define the boundry to the cavity).  Unfortunately the program does not
yet include a cavity search algorithm, so you have to tell it exactly
where the cavity is.

If you're interested, the program is available at:
ftp://hobbes.gh.wits.ac.za/pub/steric/steric_1.08.tgz

There is a readme file for installation info, and online help, but I'd
recommend you e-mail me for specific info, particularly about the cavity
volume calculation, because it's quite a new addition to the program.
The program was developed under linux unix, but has been compiled on
several other unix's with small changes to the Makefile.

Cheers, Craig

"If God had meant us to be naked, we would have been born that way."

Craig Taverner
Structural Chemistry, University of the Witwatersrand, South Africa

------------------------------------------------------------------------------
5) program VOLUME
  from [email-masked]

In my opinion, the best program to do volume calculations on
Protein structures is that written by Fred Richards (Yale U.) called
VOLUME.  It employs the Voronoi method to accomplish the volume
calculations.  You can obtain the source from Patrick Fleming:
[email-masked]. It can be compiled with ease on any Unix platform.

Cheers
-raman

                 C.S.RAMAN
         Department of Biochemistry
  University of Texas Health Science Center
           7703 Floyd Curl Drive
        San Antonio, TX 78284-7760
                    USA

          Tel:     (210) 567-6623
          Fax:     (210) 567-6595
       E-mail:  [email-masked]