From nauss@wrair-emh1.army.mil Sun Apr 7 06:00:00 1993 Message-Id: <199304071512.AA02951@oscsunb.ccl.net> Date: 7 Apr 93 11:00:00 EST From: nauss@wrair-emh1.army.mil Subject: Summary of replies about simulated annealing To: "chemistry" Good day, all - Some time ago I posed a question to the net about simulated annealing. Finally, here is a summary of responses I received. Warning: it is somewhat lengthy. Direct quotes are in parenthesis. Everything else is my edited summary. My apologies if my editing loses some of the flavor (or, God forbid, the meaning) of the responses. My thanks to all who offered opinions. My original question follows: >I am trying to refine some structural homology models of proteins. One >approach I am considering is simulated annealing. However, I want to ensure >that I understand the concept first. Please correct me if I am in error. >As I understand it, simulated annealing is simply a molecular dynamics >simulation where the protein is heated to a rather high temperature then slowly >cooled down to zero. The protein is then locked into some low energy >conformation which it was close to at the higher temperature. In order to get >accurate results, one needs to perform the simulation several times and obtain >a consensus structure. How am I doing so far? >Okay, so here are my questions. >(1) Can the procedure be implemented using the standard MSI CHARMM package or >is a special (and maybe proprietary) version needed? Has anyone a script file I >can use to learn by example? >(2) How high a temperature is needed? 300K, 600, 900, more? >(3) Any good references for learning how to use simulated annealing? >(4) Am I missing anything in my understanding of the technique? ************************************************************************************* From: Bob Funchess MOLECULAR SIMULATIONS HOTLINE SUPPORT 16 New England Executive Park Burlington, MA 01803-5297 hotline@msi.com "You are correct about simulated annealing. One thing is that you need to go to a much higher temperature such as 5000K." He also provided a much appreciated CHARMm script as an example for performing simulated annealing. I will be happy to provide the script to anyone upon request. ************************************************************************************* From "arne" (arne@mango.mef.ki.se) "I think that you are correct in your assumptions." Some other comments are: 1. "I am quite doubtfull that a sim. annealing approach will work without any "extra" information, such as NOE constrains or something else." 2. "Temperature: I am using a 500 K temperature without any cooling period for modelling BPTI and small helical segments." 3. "references: The original paper was : Brunger, Clore et al, PNAS,83,3801-3805 (1986)" ************************************************************************************* From: David C. Doherty Computational Scientist Minnesota Supercomputer Center doherty@msc.edu "Functionally, this is correct, but usually simulated annealing involves taking monte carlo steps, and following a schedule of temperature lowering. How you design that schedule (how many steps of MC or MD to take) is something of an art." Temperature is suggested to be of 700-1000K to start. ************************************************************************************* From: Georgia B. McGaughey Computational Center for Molecular Structure and Design Department of Chemistry University of Georgia, Athens, GA 30602 georgia@Huckel.chem.uga.edu Georgia provided two references for the use of SA with NMR data. 1. James TL. Relaxation Matrix Analysis of Two-Dimensional Nuclear Overhauser Effect Spectra. "Current Opinion in Structural Biology, 1, 1042 (1991). 2. Clore GM, Nilges M, Gronenborn A. Determination of Three- Dimensional Structures of Proteins in Solution by Dynamical Simulated Annealing with Interproton Distances Derived from Nuclear Magnetic Resonance Spectroscopy. Computer-Aided Molecular Design, Richard WG, ed. 203 (1989). ************************************************************************************* From: Emil Marcus Biophysics PhD Student University at Buffalo / Roswell Cancer Institute marcus@acsu.buffalo.edu "Simulated Annealing is a Monte Carlo ("random draw", "throwing the dice") method that can be quite successful in dealing with large combinatorial optimization problems, such as finding the conformation of a protein (i.e. find the position - cartesian coordinates or dihedral angles of all, or only a targeted number of atoms, such as those which are part of the backbone or side chain). The idea underlying most conformational searches is to find a set of coordinates (cartesian or dihedral) that minimize the potential energy of the system. Unfortunately, the conformational space of a protein features (very)many local energy minima... Simulated Annealing overcomes the major inconvenient of a typical gradient(derivative) - based method: that of remaining/being trapped in a local minima. SA *samples* the conformational space, prevents being trapped in local energy minima because, due to its Monte Carlo nature it is able to "jump" from one minima to another. It does not promis/guarantee the global minimum, however, if used carefully, and in combination with other search methods (such as homology...) can provide good results: consider for instance the pentapeptides, Met- and Leu- Enkephalin." "No SA option is provided (even) in the last version of Charmm, Charmm - Version 22.0.b - April, 1991, I have recently used. Neither is it available with the Amber or Ecepp force fields." ************************************************************************************* From: Lee Herman HERMAN@ULNA.BWH.HARVARD.EDU "The heating phase is a trick to push the structure into parts of the conformational surface that are dissimilar to the starting structure. This structure is then allowed to minimize (cool) to a local minimum. This final structure can be quite different locally from the "hot" sampled structure, allow in terms of tertiary structure you're right, they're probably pretty close. "Watch out when it comes to sampling conformational space "a few times". The degrees of freedom for a structure such as protein can be enormous. Adequate sampling is essential in searching for a "global minimum" (if you think it's important, that is. It may not be.). Adequate sampling is also necessary in order to properly estimate properties. Find literature on how many samples are appropriate for the kind of system you're looking at." ************************************************************************************* From: Gerard J. Kleywegt Department of Molecular Biology Biomedical Centre Sweden rd@xray.bmc.uu.se "We use this technique often while refining protein structures against crystallographic data. In those cases, we start at 3000 or even 4000 K and do a fast-cool (steps of 50 K) or a slow-cool (steps of 25 K) down to 300 K. I don't know about CHARMm, but XPLOR (which, I think, is also sold by MSI) does a good job at it." He strongly recommended using some experimental data as constraints in the SA. ************************************************************************************* From: Chris Chen Agouron Pharmaceuticals, Inc San Diego, CA 92121 chen@tbone.agouron.com "The higher the temperature, the better the calculation theoretically. 900K is a best choose when I used MMOD to do the calcs. Another thing probably need to be mentioned. When you cool down the very high temperature, you may have to consider which way is better: stepwise annealing or contiuns annealing. That will cause different results." ************************************************************************************* From: Jim Poole, Ohio University, Dept. of Chemistry jim@quanta.phy.ohiou.edu or jpoole@oucsace.cs.ohiou.edu "You have probably already gotten lots of response but here are a few references that I have found for sim.-ann. Treutlein, et al. (1992) Biochemistry 31,12726-12733 best Nilges and Brunger (1993) Proteins:Str. Fxn. Gen. 15, 133-146 Brunger (1991) Ann. Rev. Phys. Chem. 42, 197-233 Kirkpatrick, et al. (1983) Science 220, 671-680"