Re: [ccp4bb] off topic: rmsf in simulation
Different proteins do different things. Some adopt fewer conformations and a more rigid structure after binding a ligand, and others do the opposite. Haemoglobin is a nice example of a protein that becomes a lot more flexible after picking up ligands. For any reaction of the kind P + L - PL there is an entropy cost of making one molecule from two. For the protein to activate low frequency modes in the complex is one way to compensate for this by increasing the entropy of the bound form. The paper by Sturtevant (PNAS 74, 2236, 1977) is worth a read, as is Cooper and Dryden (Eur Biophys J, 11, 103, 1984), if you are interested in relating fluctuations to thermodynamics. All too often people attempt direct comparisons of structural models and affinities without realising that the so-called angstroms to calories problem often frames the question in a form that cannot be answered sensibly. For example, imagine a protease which is produced as a zymogen. Both forms may have essentially identical crystal structures even though the zymogen is more flexible. The protease can be activated by loss of vibrational modes in the unbound state which are re-awakened in the complex with substrate; hence the zymogen will have lower substrate binding and activity. You might be interested in a review by Homans (ChemBioChem 6, 1585, 2005) which discusses the use of NMR to look at entropy changes in protein-ligand binding reactions. It is by no means unusual for a residue's entropy to increase in the bound state, although in your case it seems to be the whole protein! On Dec 9, 2012, at 1:05 PM, anita p wrote: Hi All, I am trying to understand the mechanism of protein-peptide interaction in two complexes (protein-pepA and protein-pepB). While trying to perform some simulation experiments, I find that the root mean square fluctuation (RMSF) by residues of protein in the complex is higher than that of the protein alone. Please refer the figure attached to this email. pepA binds with higher affinity (in uM-range) than pepB according to invitro studies. Does this happen normally?? Please advice. Thanks in advance Anita RMSF.png
Re: [ccp4bb] off topic: rmsf in simulation
to complement the very nice description by jeremy, you may wish to try and decompose the vibrational modes to get this sense by focussing on the origins of the red shift in the vibrational spectrum and this accounts largely for the increased vibrational entropies upon complexation. This paper may be used as a guide (Dissecting the vibrational entropy change on protein/ligand binding: burial of a water molecule in bovine pancreatic trypsin inhibitor J Phys Chem B 2001 105 8050-8055) There is some very nice work by Olano Rick in JACS 2004 126:7991 on Hydration free energies and entropies for water in protein interiors. and by carol post on how the increased entropies upon complexation are the origin of the mechanism of some drugs. (for example Influence of an Antiviral Compound on the Temperature Dependence of Viral Protein Flexibility and Packing: a Molecular Dynamics Study J. Mol. Biol. (1998) 276: 331-337) Quoting Jeremy Tame jt...@tsurumi.yokohama-cu.ac.jp: Different proteins do different things. Some adopt fewer conformations and a more rigid structure after binding a ligand, and others do the opposite. Haemoglobin is a nice example of a protein that becomes a lot more flexible after picking up ligands. For any reaction of the kind P + L - PL there is an entropy cost of making one molecule from two. For the protein to activate low frequency modes in the complex is one way to compensate for this by increasing the entropy of the bound form. The paper by Sturtevant (PNAS 74, 2236, 1977) is worth a read, as is Cooper and Dryden (Eur Biophys J, 11, 103, 1984), if you are interested in relating fluctuations to thermodynamics. All too often people attempt direct comparisons of structural models and affinities without realising that the so-called angstroms to calories problem often frames the question in a form that cannot be answered sensibly. For example, imagine a protease which is produced as a zymogen. Both forms may have essentially identical crystal structures even though the zymogen is more flexible. The protease can be activated by loss of vibrational modes in the unbound state which are re-awakened in the complex with substrate; hence the zymogen will have lower substrate binding and activity. You might be interested in a review by Homans (ChemBioChem 6, 1585, 2005) which discusses the use of NMR to look at entropy changes in protein-ligand binding reactions. It is by no means unusual for a residue's entropy to increase in the bound state, although in your case it seems to be the whole protein! On Dec 9, 2012, at 1:05 PM, anita p wrote: Hi All, I am trying to understand the mechanism of protein-peptide interaction in two complexes (protein-pepA and protein-pepB). While trying to perform some simulation experiments, I find that the root mean square fluctuation (RMSF) by residues of protein in the complex is higher than that of the protein alone. Please refer the figure attached to this email. pepA binds with higher affinity (in uM-range) than pepB according to invitro studies. Does this happen normally?? Please advice. Thanks in advance Anita RMSF.png
Re: [ccp4bb] off topic: rmsf in simulation
Hi All thanks for your detailed reply. A higher RMSF(as I showed in the png.) *doesnot *mean that the RMSD for Calpha backbone showed be high. Am I correct ?? Because in my case the backbone RMSD for the receptor of the peptide bound structure is lower than the receptor alone. Because I wanted to know if my simulations have gone fine. thanks again in advance. Anita On Sun, Dec 9, 2012 at 6:44 PM, Chandra Verma chan...@bii.a-star.edu.sgwrote: to complement the very nice description by jeremy, you may wish to try and decompose the vibrational modes to get this sense by focussing on the origins of the red shift in the vibrational spectrum and this accounts largely for the increased vibrational entropies upon complexation. This paper may be used as a guide (Dissecting the vibrational entropy change on protein/ligand binding: burial of a water molecule in bovine pancreatic trypsin inhibitor J Phys Chem B 2001 105 8050-8055) There is some very nice work by Olano Rick in JACS 2004 126:7991 on Hydration free energies and entropies for water in protein interiors. and by carol post on how the increased entropies upon complexation are the origin of the mechanism of some drugs. (for example Influence of an Antiviral Compound on the Temperature Dependence of Viral Protein Flexibility and Packing: a Molecular Dynamics Study J. Mol. Biol. (1998) 276: 331-337) Quoting Jeremy Tame jt...@tsurumi.yokohama-cu.ac.**JPjt...@tsurumi.yokohama-cu.ac.jp : Different proteins do different things. Some adopt fewer conformations and a more rigid structure after binding a ligand, and others do the opposite. Haemoglobin is a nice example of a protein that becomes a lot more flexible after picking up ligands. For any reaction of the kind P + L - PL there is an entropy cost of making one molecule from two. For the protein to activate low frequency modes in the complex is one way to compensate for this by increasing the entropy of the bound form. The paper by Sturtevant (PNAS 74, 2236, 1977) is worth a read, as is Cooper and Dryden (Eur Biophys J, 11, 103, 1984), if you are interested in relating fluctuations to thermodynamics. All too often people attempt direct comparisons of structural models and affinities without realising that the so-called angstroms to calories problem often frames the question in a form that cannot be answered sensibly. For example, imagine a protease which is produced as a zymogen. Both forms may have essentially identical crystal structures even though the zymogen is more flexible. The protease can be activated by loss of vibrational modes in the unbound state which are re-awakened in the complex with substrate; hence the zymogen will have lower substrate binding and activity. You might be interested in a review by Homans (ChemBioChem 6, 1585, 2005) which discusses the use of NMR to look at entropy changes in protein-ligand binding reactions. It is by no means unusual for a residue's entropy to increase in the bound state, although in your case it seems to be the whole protein! On Dec 9, 2012, at 1:05 PM, anita p wrote: Hi All, I am trying to understand the mechanism of protein-peptide interaction in two complexes (protein-pepA and protein-pepB). While trying to perform some simulation experiments, I find that the root mean square fluctuation (RMSF) by residues of protein in the complex is higher than that of the protein alone. Please refer the figure attached to this email. pepA binds with higher affinity (in uM-range) than pepB according to invitro studies. Does this happen normally?? Please advice. Thanks in advance Anita RMSF.png
[ccp4bb] off topic: rmsf in simulation
Hi All, I am trying to understand the mechanism of protein-peptide interaction in two complexes (protein-pepA and protein-pepB). While trying to perform some simulation experiments, I find that the* root mean square fluctuation (RMSF) by residues of protein in the complex is higher than that of the protein alone.* Please refer the figure attached to this email. pepA binds with higher affinity (in uM-range) than pepB according to invitro studies. Does this happen normally?? Please advice. Thanks in advance Anita attachment: RMSF.png
