scholarly journals Protein Flexibility Reduces Solvent-Mediated Friction Barriers of Ligand Binding to a Hydrophobic Surface Patch

2021 ◽  
Author(s):  
Christopher Päslack ◽  
Lars V Schäfer ◽  
Matthias Heyden
Keyword(s):  
Ligand Binding ◽  
Protein Flexibility ◽  
Hydrophobic Surface ◽  
Model Systems ◽  
Surface Patch ◽  
Protein Motions ◽  
Internal Protein

Solvent fluctuations have been explored in detail for idealized and rigid hydrophobic model systems, but so far it has remained unclear how internal protein motions and their coupling to the...

scholarly journals The role of water and protein flexibility in the structure-based virtual screening of allosteric GPCR modulators: an mGlu5 receptor case study

2019 ◽  
Vol 33 (9) ◽  
pp. 787-797 ◽  
Author(s):  
Zoltán Orgován ◽  
György G. Ferenczy ◽  
György M. Keserű
Keyword(s):  
Virtual Screening ◽  
Ligand Binding ◽  
Conformational Changes ◽  
Metabotropic Glutamate Receptor ◽  
Protein Structures ◽  
Protein Flexibility ◽  
Water Molecules ◽  
Large Set ◽  
Allosteric Modulators

Abstract Stabilizing unique receptor conformations, allosteric modulators of G-protein coupled receptors (GPCRs) might open novel treatment options due to their new pharmacological action, their enhanced specificity and selectivity in both binding and signaling. Ligand binding occurs at intrahelical allosteric sites and involves significant induced fit effects that include conformational changes in the local protein environment and water networks. Based on the analysis of available crystal structures of metabotropic glutamate receptor 5 (mGlu5) we investigated these effects in the binding of mGlu5 receptor negative allosteric modulators. A large set of retrospective virtual screens revealed that the use of multiple protein structures and the inclusion of selected water molecules improves virtual screening performance compared to conventional docking strategies. The role of water molecules and protein flexibility in ligand binding can be taken into account efficiently by the proposed docking protocol that provided reasonable enrichment of true positives. This protocol is expected to be useful also for identifying intrahelical allosteric modulators for other GPCR targets.

scholarly journals Protein stability induced by ligand binding correlates with changes in protein flexibility

2003 ◽  
Vol 12 (7) ◽  
pp. 1496-1506 ◽  
Author(s):  
María Soledad Celej ◽  
Guillermo G. Montich ◽  
Gerardo D. Fidelio
Keyword(s):  
Ligand Binding ◽  
Protein Stability ◽  
Protein Flexibility

scholarly journals GPCRs through the keyhole: the role of protein flexibility in ligand binding to β-adrenoceptors

2016 ◽  
Vol 35 (12) ◽  
pp. 2604-2619 ◽  
Author(s):  
Abigail L. Emtage ◽  
Shailesh N. Mistry ◽  
Peter M. Fischer ◽  
Barrie Kellam ◽  
Charles A. Laughton
Keyword(s):  
Ligand Binding ◽  
Protein Flexibility

scholarly journals High-Order Correlations in Internal Protein Motions and Energetics

2010 ◽  
Vol 98 (3) ◽  
pp. 235a-236a
Author(s):  
Arvind Ramanathan ◽  
Andrej Savol ◽  
Chris Langmead ◽  
Pratul Agarwal ◽  
S. Chakra Chennubhotla
Keyword(s):  
High Order ◽  
Protein Motions ◽  
Internal Protein

scholarly journals Binding thermodynamics of host-guest systems with SMIRNOFF99Frosst 1.0.5 from the Open Force Field Initiative

2019 ◽  
Author(s):  
David Slochower ◽  
Niel Henriksen ◽  
Lee-Ping Wang ◽  
John Chodera ◽  
David Mobley ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Force Field ◽  
Small Molecule ◽  
Force Fields ◽  
Free Energy Calculations ◽  
Model Systems ◽  
Conformational Space ◽  
Free Energies ◽  
Binding Thermodynamics ◽  
Binding Free Energies

<div><div><div><p>Designing ligands that bind their target biomolecules with high affinity and specificity is a key step in small- molecule drug discovery, but accurately predicting protein-ligand binding free energies remains challenging. Key sources of errors in the calculations include inadequate sampling of conformational space, ambiguous protonation states, and errors in force fields. Noncovalent complexes between a host molecule with a binding cavity and a drug-like guest molecules have emerged as powerful model systems. As model systems, host-guest complexes reduce many of the errors in more complex protein-ligand binding systems, as their small size greatly facilitates conformational sampling, and one can choose systems that avoid ambiguities in protonation states. These features, combined with their ease of experimental characterization, make host-guest systems ideal model systems to test and ultimately optimize force fields in the context of binding thermodynamics calculations.</p><p><br></p><p>The Open Force Field Initiative aims to create a modern, open software infrastructure for automatically generating and assessing force fields using data sets. The first force field to arise out of this effort, named SMIRNOFF99Frosst, has approximately one tenth the number of parameters, in version 1.0.5, compared to typical general small molecule force fields, such as GAFF. Here, we evaluate the accuracy of this initial force field, using free energy calculations of 43 α and β-cyclodextrin host-guest pairs for which experimental thermodynamic data are available, and compare with matched calculations using two versions of GAFF. For all three force fields, we used TIP3P water and AM1-BCC charges. The calculations are performed using the attach-pull-release (APR) method as implemented in the open source package, pAPRika. For binding free energies, the root mean square error of the SMIRNOFF99Frosst calculations relative to experiment is 0.9 [0.7, 1.1] kcal/mol, while the corresponding results for GAFF 1.7 and GAFF 2.1 are 0.9 [0.7, 1.1] kcal/mol and 1.7 [1.5, 1.9] kcal/mol, respectively, with 95% confidence ranges in brackets. These results suggest that SMIRNOFF99Frosst performs competitively with existing small molecule force fields and is a parsimonious starting point for optimization.</p></div></div></div>

scholarly journals Ligand Binding Sites of Inducible Costimulator and High Avidity Mutants with Improved Function

2002 ◽  
Vol 195 (8) ◽  
pp. 1033-1041 ◽  
Author(s):  
Shengdian Wang ◽  
Gefeng Zhu ◽  
Koji Tamada ◽  
Lieping Chen ◽  
Jürgen Bajorath
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Ligand Binding ◽  
Binding Sites ◽  
T Cell Response ◽  
Surface Patch ◽  
High Avidity ◽  
Wild Type ◽  
Ligand Interaction ◽  
Inducible Costimulator

Interaction between inducible costimulator (ICOS) and its ligand is implicated in the induction of cell-mediated and humoral immune responses. However, the molecular details of this interaction are unknown. We report here a mutagenesis analysis of residues in ICOS that are critical for ligand binding. A three-dimensional model of the extracellular immunoglobulin-like domain of ICOS was used to map the residues conserved within the CD28 family. This analysis identified a surface patch containing the characteristic “PPP” sequence and is conserved in human and mouse ICOS. Mutations in this region of human ICOS reduce or abolish ligand binding. Our results suggest that the ligand binding site in ICOS maps to a region overlapping yet distinct from the CD80/CD86 binding sites in CD28 and cytotoxic T lymphocyte antigen (CTLA)-4. Thus, the analysis suggests that differences in ligand binding specificity between these related costimulatory molecules have evolved by utilization of overlapping regions with different patterns of conserved and nonconserved residues. Two site-specific mutants generated in the course of our studies bound ICOS ligand with higher avidity than wild-type ICOS. An S76E mutant protein of ICOS blocked T cell costimulatory function of ICOS ligand and inhibited T cell response to allogeneic antigens superior to wild-type ICOS. Our studies thus identified critical residues involving in ICOS receptor–ligand interaction and provide new modulators for immune responses.

scholarly journals Electrostatic Modulation in Steroid Receptor Recruitment of LXXLL and FXXLF Motifs

2003 ◽  
Vol 23 (6) ◽  
pp. 2135-2150 ◽  
Author(s):  
Bin He ◽  
Elizabeth M. Wilson
Keyword(s):  
Ligand Binding ◽  
Steroid Receptors ◽  
Interaction Model ◽  
Hydrophobic Surface ◽  
Steroid Receptor ◽  
Activation Function ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Charged Residues ◽  
Oppositely Charged

ABSTRACT Coactivator recruitment by activation function 2 (AF2) in the steroid receptor ligand binding domain takes place through binding of an LXXLL amphipathic α-helical motif at the AF2 hydrophobic surface. The androgen receptor (AR) and certain AR coregulators are distinguished by an FXXLF motif that interacts selectively with the AR AF2 site. Here we show that LXXLL and FXXLF motif interactions with steroid receptors are modulated by oppositely charged residues flanking the motifs and charge clusters bordering AF2 in the ligand binding domain. An increased number of charged residues flanking AF2 in the ligand binding domain complement the two previously characterized charge clamp residues in coactivator recruitment. The data suggest a model whereby coactivator recruitment to the receptor AF2 surface is initiated by complementary charge interactions that reflect a reversal of the acidic activation domain-coactivator interaction model.

scholarly journals Protein Flexibility and Ligand Rigidity: A Thermodynamic and Kinetic Study of ITAM-Based Ligand Binding to Syk Tandem SH2

ChemBioChem ◽  
2005 ◽  
Vol 6 (12) ◽  
pp. 2261-2270 ◽  
Author(s):  
Nico J. de Mol ◽  
M. Isabel Catalina ◽  
Frank J. Dekker ◽  
Marcel J. E. Fischer ◽  
Albert J. R. Heck ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Kinetic Study ◽  
Protein Flexibility
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