BioNMR
NMR aggregator & online community since 2003
BioNMR    
Learn or help to learn NMR - get free NMR books!
 

Go Back   BioNMR > Educational resources > Journal club
Advanced Search



Jobs Groups Conferences Literature Pulse sequences Software forums Programs Sample preps Web resources BioNMR issues


Webservers
NMR processing:
MDD
NMR assignment:
Backbone:
Autoassign
MARS
UNIO Match
PINE
Side-chains:
UNIO ATNOS-Ascan
NOEs:
UNIO ATNOS-Candid
UNIO Candid
ASDP
Structure from NMR restraints:
Ab initio:
GeNMR
Cyana
XPLOR-NIH
ASDP
UNIO ATNOS-Candid
UNIO Candid
Fragment-based:
BMRB CS-Rosetta
Rosetta-NMR (Robetta)
Template-based:
GeNMR
I-TASSER
Refinement:
Amber
Structure from chemical shifts:
Fragment-based:
WeNMR CS-Rosetta
BMRB CS-Rosetta
Homology-based:
CS23D
Simshift
Torsion angles from chemical shifts:
Preditor
TALOS
Promega- Proline
Secondary structure from chemical shifts:
CSI (via RCI server)
TALOS
MICS caps, β-turns
d2D
PECAN
Flexibility from chemical shifts:
RCI
Interactions from chemical shifts:
HADDOCK
Chemical shifts re-referencing:
Shiftcor
UNIO Shiftinspector
LACS
CheckShift
RefDB
NMR model quality:
NOEs, other restraints:
PROSESS
PSVS
RPF scores
iCing
Chemical shifts:
PROSESS
CheShift2
Vasco
iCing
RDCs:
DC
Anisofit
Pseudocontact shifts:
Anisofit
Protein geomtery:
Resolution-by-Proxy
PROSESS
What-If
iCing
PSVS
MolProbity
SAVES2 or SAVES4
Vadar
Prosa
ProQ
MetaMQAPII
PSQS
Eval123D
STAN
Ramachandran Plot
Rampage
ERRAT
Verify_3D
Harmony
Quality Control Check
NMR spectrum prediction:
FANDAS
MestReS
V-NMR
Flexibility from structure:
Backbone S2
Methyl S2
B-factor
Molecular dynamics:
Gromacs
Amber
Antechamber
Chemical shifts prediction:
From structure:
Shiftx2
Sparta+
Camshift
CH3shift- Methyl
ArShift- Aromatic
ShiftS
Proshift
PPM
CheShift-2- Cα
From sequence:
Shifty
Camcoil
Poulsen_rc_CS
Disordered proteins:
MAXOCC
Format conversion & validation:
CCPN
From NMR-STAR 3.1
Validate NMR-STAR 3.1
NMR sample preparation:
Protein disorder:
DisMeta
Protein solubility:
camLILA
ccSOL
Camfold
camGroEL
Zyggregator
Isotope labeling:
UPLABEL
Solid-state NMR:
sedNMR


Reply
Thread Tools Search this Thread Rate Thread Display Modes
  #1  
Unread 08-14-2010, 05:56 AM
nmrlearner's Avatar
Senior Member
 
Join Date: Jan 2005
Posts: 23,135
Points: 193,617, Level: 100
Points: 193,617, Level: 100 Points: 193,617, Level: 100 Points: 193,617, Level: 100
Level up: 0%, 0 Points needed
Level up: 0% Level up: 0% Level up: 0%
Activity: 50.7%
Activity: 50.7% Activity: 50.7% Activity: 50.7%
Last Achievements
Award-Showcase
NMR Credits: 0
NMR Points: 193,617
Downloads: 0
Uploads: 0
Default Constraining Binding Hot Spots: NMR and Molecular Dynamics Simulations Provide a Stru

Constraining Binding Hot Spots: NMR and Molecular Dynamics Simulations Provide a Structural Explanation for Enthalpy−Entropy Compensation in SH2−Ligand Binding




Joshua M. Ward, Nina M. Gorenstein, Jianhua Tian, Stephen F. Martin and Carol Beth Post*
Department of Medicinal Chemistry, Markey Center for Structural Biology, and Purdue Cancer Center, Purdue University, West Lafayette, Indiana 47907, and Department of Chemistry and Biochemistry and The Institute of Cellular and Molecular Biology, The University of Texas, Austin, Texas 78712









NMR spectroscopy and molecular dynamics (MD) simulations were used to probe the structure and dynamics of complexes of three phosphotyrosine-derived peptides with the Src SH2 domain in an effort to uncover a structural explanation for enthalpy−entropy compensation observed in the binding thermodynamics. The series of phosphotyrosine peptide derivatives comprises the natural pYEEI Src SH2 ligand, a constrained mimic, in which the phosphotyrosine (pY) residue is preorganized in the bound conformation for the purpose of gaining an entropic advantage to binding, and a flexible analogue of the constrained mimic. The expected gain in binding entropy of the constrained mimic was realized; however, a balancing loss in binding enthalpy was also observed that could not be rationalized from the crystallographic structures. We examined protein dynamics to evaluate whether the observed enthalpic penalty might be the result of effects arising from altered motions in the complex. 15N-relaxation studies and positional fluctuations from molecular dynamics indicate that the main-chain dynamics of the protein show little variation among the three complexes. Root mean squared (rms) coordinate deviations vary by less than 1.5 Ċ for all non-hydrogen atoms for the crystal structures and in the ensemble average structures calculated from the simulations. In contrast to this striking similarity in the structures and dynamics, there are a number of large chemical shift differences from residues across the binding interface, but particularly from key Src SH2 residues that interact with pY, the “hot spot” residue, which contributes about one-half of the binding free energy. Rank-order correlations between chemical shifts and ligand binding enthalpy for several pY-binding residues, coupled with available mutagenesis and calorimetric data, suggest that subtle structural perturbations (<1 Ċ) from the conformational constraint of the pY residue sufficiently alter the geometry of enthalpically critical interactions in the binding pocket to cause the loss of binding enthalpy, leading to the observed enthalpy−entropy compensation. We find no evidence to support the premise that enthalpy−entropy compensation is an inherent property and conclude that preorganization of Src SH2 ligand residues involved in binding hot spots may eventuate in suboptimal interactions with the domain. We propose that introducing constraints elsewhere in the ligand could minimize enthalpy−entropy compensation effects. The results illustrate the utility of the NMR chemical shift to highlight small, but energetically significant, perturbations in structure that might otherwise go unnoticed in an apparently rigid protein.

Journal of the American Chemical Society, Volume 132, Issue 32, Page 11058-11070, August 18, 2010.

Source: JACS
Reply With Quote


Did you find this post helpful? Yes | No

Reply
Similar Threads
Thread Thread Starter Forum Replies Last Post
Membrane binding of an acyl-lactoferricin B antimicrobial peptide from solid-state NMR experiments and molecular dynamics simulations.
Membrane binding of an acyl-lactoferricin B antimicrobial peptide from solid-state NMR experiments and molecular dynamics simulations. Membrane binding of an acyl-lactoferricin B antimicrobial peptide from solid-state NMR experiments and molecular dynamics simulations. Biochim Biophys Acta. 2011 Aug;1808(8):2019-30 Authors: Romo TD, Bradney LA, Greathouse DV, Grossfield A Abstract One approach to the growing health problem of antibiotic resistant bacteria is the development of antimicrobial peptides (AMPs) as alternative treatments. The...
nmrlearner Journal club 0 08-19-2011 02:56 PM
Structure and Dynamics of the A?21–30 Peptide from the Interplay of NMR Experiments and Molecular Simulations
Structure and Dynamics of the A?21–30 Peptide from the Interplay of NMR Experiments and Molecular Simulations Nicolas L. Fawzi, Aaron H. Phillips, Jory Z. Ruscio, Michaeleen Doucleff, David E. Wemmer and Teresa Head-Gordon Journal of the American Chemical Society DOI: 10.1021/ja204315n http://feeds.feedburner.com/~ff/acs/jacsat?d=yIl2AUoC8zA http://feeds.feedburner.com/~r/acs/jacsat/~4/bEQEah_ik60
nmrlearner Journal club 0 07-09-2011 07:11 AM
[NMR paper] Molecular dynamics simulations of protein G challenge NMR-derived correlated backbone
Molecular dynamics simulations of protein G challenge NMR-derived correlated backbone motions. Related Articles Molecular dynamics simulations of protein G challenge NMR-derived correlated backbone motions. Angew Chem Int Ed Engl. 2005 May 30;44(22):3394-9 Authors: Lange OF, Grubmüller H, de Groot BL
nmrlearner Journal club 0 11-25-2010 08:21 PM
[NMR paper] NMR-detected hydrogen exchange and molecular dynamics simulations provide structural
NMR-detected hydrogen exchange and molecular dynamics simulations provide structural insight into fibril formation of prion protein fragment 106-126. Related Articles NMR-detected hydrogen exchange and molecular dynamics simulations provide structural insight into fibril formation of prion protein fragment 106-126. Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):14790-5 Authors: Kuwata K, Matumoto T, Cheng H, Nagayama K, James TL, Roder H PrP106-126, a peptide corresponding to residues 107-127 of the human prion protein, induces neuronal cell...
nmrlearner Journal club 0 11-24-2010 09:16 PM
[NMR paper] Molecular dynamics simulations of photoactive yellow protein (PYP) in three states of
Molecular dynamics simulations of photoactive yellow protein (PYP) in three states of its photocycle: a comparison with X-ray and NMR data and analysis of the effects of Glu46 deprotonation and mutation. Related Articles Molecular dynamics simulations of photoactive yellow protein (PYP) in three states of its photocycle: a comparison with X-ray and NMR data and analysis of the effects of Glu46 deprotonation and mutation. Eur Biophys J. 2002 Dec;31(7):504-20 Authors: Antes I, Thiel W, van Gunsteren WF Photoactive yellow protein (PYP) is a...
nmrlearner Journal club 0 11-24-2010 08:58 PM
[NMR paper] The solution conformations of amino acids from molecular dynamics simulations of Gly-
The solution conformations of amino acids from molecular dynamics simulations of Gly-X-Gly peptides: comparison with NMR parameters. Related Articles The solution conformations of amino acids from molecular dynamics simulations of Gly-X-Gly peptides: comparison with NMR parameters. Biochem Cell Biol. 1998;76(2-3):164-70 Authors: van der Spoel D The conformations that amino acids can adopt in the random coil state are of fundamental interest in the context of protein folding research and studies of protein-peptide interactions. To date, no...
nmrlearner Journal club 0 11-17-2010 11:06 PM
Constraining Binding Hot Spots: NMR and Molecular Dynamics Simulations Provide a Stru
Constraining Binding Hot Spots: NMR and Molecular Dynamics Simulations Provide a Structural Explanation for Enthalpy-Entropy Compensation in SH2-Ligand Binding. Related Articles Constraining Binding Hot Spots: NMR and Molecular Dynamics Simulations Provide a Structural Explanation for Enthalpy-Entropy Compensation in SH2-Ligand Binding. J Am Chem Soc. 2010 Aug 18;132(32):11058-70 Authors: Ward JM, Gorenstein NM, Tian J, Martin SF, Post CB NMR spectroscopy and molecular dynamics (MD) simulations were used to probe the structure and dynamics...
nmrlearner Journal club 0 08-17-2010 03:36 AM
Using NMR Chemical Shifts as Structural Restraints in Molecular Dynamics Simulations
Using NMR Chemical Shifts as Structural Restraints in Molecular Dynamics Simulations of Proteins. Related Articles Using NMR Chemical Shifts as Structural Restraints in Molecular Dynamics Simulations of Proteins. Structure. 2010 Aug 11;18(8):923-933 Authors: Robustelli P, Kohlhoff K, Cavalli A, Vendruscolo M We introduce a procedure to determine the structures of proteins by incorporating NMR chemical shifts as structural restraints in molecular dynamics simulations. In this approach, the chemical shifts are expressed as differentiable...
nmrlearner Journal club 0 08-17-2010 03:36 AM


Thread Tools Search this Thread
Search this Thread:

Advanced Search
Display Modes Rate This Thread
Rate This Thread:

Posting Rules
You may not post new threads
You may not post replies
You may not post attachments
You may not edit your posts

BB code is On
Smilies are On
[IMG] code is On
HTML code is On
Trackbacks are Off
Pingbacks are Off
Refbacks are Off



BioNMR advertisements to pay for website hosting and domain registration. Nobody does it for us.



Powered by vBulletin® Version 3.7.3
Copyright ©2000 - 2024, Jelsoft Enterprises Ltd.
Copyright, BioNMR.com, 2003-2013
Search Engine Friendly URLs by vBSEO 3.6.0

All times are GMT. The time now is 06:02 AM.


Map