From owner-chemistry@ccl.net Fri Sep 12 05:48:00 2008 From: "Vincent Leroux vincent.leroux]![loria.fr" <owner-chemistry%%server.ccl.net> To: CCL Subject: CCL: comparison between 2 different structures Message-Id: <-37744-080912045649-5282-8teP1pLOtMmKbNL5aCd0IA%%server.ccl.net> X-Original-From: Vincent Leroux <vincent.leroux\a/loria.fr> Content-Transfer-Encoding: 8bit Content-Type: text/plain; charset=ISO-8859-1; format=flowed Date: Fri, 12 Sep 2008 10:56:46 +0200 MIME-Version: 1.0 Sent to CCL by: Vincent Leroux [vincent.leroux!A!loria.fr] Hi Vivek, You are trying to get the absolute low energy state of two similar molecules, this means you try to find their state in vacuum at 0K. I suppose you are in a protein-ligand context, bear in mind your small molecules will act on their target at 300K, your system being solvated... You do not have a single conformation then, but an ensemble of thermodynamically-accessible states (landscapes as you say). You are right being cautious as using only the (assumed) lowest energy state to describe the global "stability" of your molecules is a bit oversimplified. As you mention protein-ligand complexes I suppose you are in the drug design context. Rather than performing complex minimizations / conformational searches it could be more useful to compute basic properties to check Lipinski's rule-of-five, try toxicity prediction algorithms if you have them, make sure the chemists can actually make the compounds, and so on... No molecular modelling at this point - you just want to check that there is nothing stopping you from discarding your candidates before going further. Drug designers do not want to waste their time on useless compounds ;-) When you study protein-ligand complexes, bear in mind that the free energy of binding is what describes best the strength of the protein-ligand interaction, the interaction energy being only a small part of it (the simplest to compute indeed)... Calculating free energy of binding rigorously is very difficult - get the "Free energy calculations" book edited by C.Chipot and A.Pohorille if you want to try. You can compare interaction energy between two ligands bound to the same protein, this is similar to ranking compounds according to docking scores after a virtual screening experiment, but... - is your single protein-ligand conformation enough to describe the entire energy landscape of the system? - is the complex stable at 300K and solvated? - is the forcefield used to compute the interaction energy (= nonbonded terms) okay? - how flexible the protein active site can be upon ligand binding (induced fit effects)? - are you sure you located the active site correctly? - is the protein geometry reliable? (resolution of experimental data? homology modelling details?) - is it possible that discrete water molecules actively take part in the protein-ligand binding? - are the free energy of binding terms you do not consider of the same order between the two ligands? - ... Performing at least 1 ns of MD (CHARMM or AMBER FF) of the two protein-ligand complexes in explicit solvent, 300K, no constraint, can answer many questions (but not all - given in many cases it can answer ***enough*** questions, this is fine). You should search for papers at this point to gain knowledge, before planning such an heavy calculation. Remember that at best you will be able to state that ligand A has a significant probability of being more potent to target X than ligand B. You can always be wrong - there are so many aspects of protein-ligand binding that are not taken into account at this stage... Good luck :-) VL Vivek Sharma vivek.viv.sharma::gmail.com a �crit : > Sent to CCL by: "Vivek Sharma" [vivek.viv.sharma ~ gmail.com] > Dear CCL people, > > I have one conceptual question to ask, may be its trivial but all your comments will be very helpful in understanding more about this field and will obviosuly correct some doubts. > > Lets say I have two different ligand molecules (different substituents on some common core). I sketch them, do conformational analysis on those and minimise the energy of both the systems separately and finally some values of total potential energy are obtained. And, if one value is lower than the other, can I say that this molecule (with lower potential energy) is more stable than the other one? > I have mixed thoughts about it. I would assume if there have been a single compound, one can compare the potential energies of the compound in two different tautomeric states for example. But in case of two different compounds, which will have different potential energy landscapes, etc, it may not be possible. > My this query also scales-up to a docking study where a similar question arises, i.e. can I compare the Binding Energy or Interaction Energy between two different Protein Ligand complexes (where protein is same in both, but ligands are chemically different).? > > thanks in advance, > > Vivek > IMM, Pune, India. > >