Introduction to Molecular Recognition Models

Schneider, H.

doi:10.1002/3527601813.ch2

Cited by 4 publications

(1 citation statement)

References 66 publications

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“…This supports approaches such as docking, that model interactions taking place in the near vicinity of a ligand binding site. However, protein–ligand interaction is also known to be affected by amino acids not in direct contact with the ligand 31, 32. Our approach makes it possible to model both protein–ligand interactions caused by amino acids in contact with the ligand and amino acids further away in space, which may explain why our models can generalize over a wide range of proteins in terms of size and fold.…”

Section: Discussionmentioning

confidence: 99%

Generalized modeling of enzyme–ligand interactions using proteochemometrics and local protein substructures

et al. 2006

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Modeling and understanding protein-ligand interactions is one of the most important goals in computational drug discovery. To this end, proteochemometrics uses structural and chemical descriptors from several proteins and several ligands to induce interaction-models. Here, we present a new and generalized approach in which proteins varying greatly in terms of sequence and structure are represented by a library of local substructures. Using linear regression and rule-based learning, we combine such local substructures with chemical descriptors from the ligands to model binding affinity for a training set of hydrolase and lyase enzymes. We evaluate the predictive performance of these models using cross validation and sets of unseen ligand with unknown three-dimensional structure. The models are shown to generalize by outperforming models using descriptors from only proteins or only ligands, or models using global structure similarities rather than local similarities. Thus, we demonstrate that this approach is capable of describing dependencies between local structural properties and ligands in otherwise dissimilar protein structures. These dependencies are often, but not always, associated with local substructures that are in contact with the ligands. Finally, we show that strongly bound enzyme-ligand complexes require the presence of particular local substructures, while weakly bound complexes may be described by the absence of certain properties. The results demonstrate that the alignment-independent approach using local substructures is capable of describing protein-ligand interaction for largely different proteins and hence opens up for proteochemometrics-analysis of the interaction-space of entire proteomes. Current approaches are limited to families of closely related proteins. families of closely related proteins.

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Section: Discussionmentioning

confidence: 99%

Generalized modeling of enzyme–ligand interactions using proteochemometrics and local protein substructures

et al. 2006

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Controlling Supramolecular Assembly Using Electronic Effects

Aakeröy

Epa

2011

Electronic Effects in Organic Chemistry

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Through systematic structural studies using custom designed probe molecules, it has been shown that the balance between hydrogen-bonds in the context of supramolecular chemistry and crystal engineering can be understood and guided by a semiquantitative thermodynamic assessment that integrates theoretical and experimental views of solution-based molecular recognition events. Although pKa values can be used for ranking hydrogen-bond donors/acceptors within a family of compounds, they do not offer reliable information when comparing different functional groups. However, against a backdrop of a simple electrostatic interpretation of hydrogen bonds coupled with a focus on the primary non-covalent interactions, molecular electrostatic potential surfaces can be employed for guiding the synthesis of binary- and ternary co-crystals with the desired connectivity and dimensionality.

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

et al. 2010

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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 analog 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 Å 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 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 Å) 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 entropy-enthalpy 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 entropy-enthalpy 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.

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Introduction to Molecular Recognition Models

Cited by 4 publications

References 66 publications

Generalized modeling of enzyme–ligand interactions using proteochemometrics and local protein substructures

Generalized modeling of enzyme–ligand interactions using proteochemometrics and local protein substructures

Controlling Supramolecular Assembly Using Electronic Effects

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

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