Modeling protein-small molecule interactions: structure and thermodynamics of noble gases binding in a cavity in mutant phage T4 Lysozyme L99A

Mann, Geoffrey; Hermans, Jan

doi:10.1006/jmbi.2000.4064

Cited by 55 publications

(83 citation statements)

References 35 publications

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“…The present PMF-based approach avoids the double-decoupling scheme (12)(13)(14)(15)(16)(17), which can lead to significant difficulties in the case of highly charged ligands. Exact and computationally advantageous expressions for the equilibrium binding constant were derived directly from configurational ensemble averages.…”

Section: Resultsmentioning

confidence: 99%

“…In the present calculations, the binding constant was expressed as a step-by-step reversible process, and the ligand-receptor PMF reporting the reversible work to translate the ligand from the bulk solution to the bound state is a central quantity. The alternative ''double-decoupling'' scheme (12)(13)(14)(15)(16)(17)43) augmented by various restraining potentials is particularly advantageous for computing the binding constant of a ligand bound inside a pocket located deeply in the interior of a protein because it does not require any consideration of the pathway leading from the bulk to the binding site. Nonetheless, this method is nearly impractical when the absolute solvation free energy of the ligand is very large because the binding free energy then is computed as the (small) difference between two very large numbers.…”

Section: [14]mentioning

confidence: 99%

“…Nonetheless, although previous studies have provided many of the fundamental elements necessary for the calculation of binding free energy by means of MD (12)(13)(14)(15)(16)(17), the computations so far have been limited mostly to fairly small and rigid ligands [e.g., rare gas atom (12,15), water (14), camphor (13), benzene (15), and a single amino acid (16)], and some aspects require further considerations. The challenges that lie ahead are well illustrated by considering the association of peptide ligands to Src homology 2 (SH2) domains.…”

mentioning

confidence: 99%

“…First, the sheer magnitude of the electrostatics interactions arising from the doubly charged phosphotyrosine side chain (28) suggests that the standard FEP technique used to compute absolute binding free energies, which consists of reversibly decoupling the ligand from its surrounding (12)(13)(14)(15)(16)(17), is essentially impractical. Furthermore, additional difficulties are expected to arise from the significant conformational flexibility of the unbound peptide ligand in solution.…”

mentioning

confidence: 99%

“…In the present case, the absolute binding free energy is rigorously expressed as the sum of separate contributions corresponding to a step-by-step process describing the association of the ligand with the receptor. The formulation relies on potential of mean force (PMF) techniques designed to avoid the problems associated with large free energies involved in the standard FEP decoupling schemes (12)(13)(14)(15)(16)(17). As an illustration of the present treatment, the absolute binding free energy of the phosphotyrosyl peptide Ace-pYEEI to the SH2 domain of Lck kinase is computed.…”

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confidence: 99%

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Calculation of absolute protein–ligand binding free energy from computer simulations

Woo

Roux²

2005

Proc. Natl. Acad. Sci. U.S.A.

634

896

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A general methodology for calculating the equilibrium binding constant of a flexible ligand to a protein receptor is formulated on the basis of potentials of mean force. The overall process is decomposed into several stages that can be computed separately: the free ligand in the bulk is first restrained into the conformation it adopts in the bound state, position, and orientation by applying biasing potentials, then it is translated into the binding site, where it is released completely. The conformational restraining potential is based on the root-mean-square deviation of the peptide coordinates relative to its average conformation in the bound complex. Free energy contributions from each stage are calculated by means of free energy perturbation potential of mean force techniques by using appropriate order parameters. The present approach avoids the need to decouple the ligand from its surrounding (bulk solvent and receptor protein) as is traditionally performed in the doubledecoupling scheme. It is believed that the present formulation will be particularly useful when the solvation free energy of the ligand is very large. As an application, the equilibrium binding constant of the phosphotyrosine peptide pYEEI to the Src homology 2 domain of human Lck has been calculated. The results are in good agreement with experimental values. Approaches at different levels of complexity and sophistication have been used to calculate binding free energies in complex biomolecular systems. Screening of large molecular databases of compounds to identify potential lead drug molecules typically relies on very simplified scoring schemes to achieve the needed efficiency (6). The binding free energy may be estimated on the basis of a continuum solvent approximation assuming quadratic fluctuations around a unique configuration (7,8). The Molecular Mechanics͞ Poisson-Boltzmann (PB) and Surface Area (MM͞PB-SA) method is a popular approach that relies on a mixed scheme combining configurations sampled from molecular dynamics (MD) simulations with explicit solvent, together with free energy estimators based on an implicit continuum solvent model (9). MM͞PB-SA shares some similarities with the linear interaction energy method, which also uses averages calculated from explicit solvent simulations within a linear response framework (10). Despite their usefulness, such approximate schemes can be limited, and how to improve the results is unclear because they do not offer a rigorous route to compute the equilibrium binding constant.In principle, treatments based on MD free energy perturbation (FEP) simulations with explicit solvent molecules offer the most powerful and promising approach to estimate the binding free energies of ligands to macromolecules (11). Nonetheless, although previous studies have provided many of the fundamental elements necessary for the calculation of binding free energy by means of MD (12-17), the computations so far have been limited mostly to fairly small and rigid ligands [e.g., rare gas atom (12, 15), water (14)...

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Section: Resultsmentioning

confidence: 99%

Section: [14]mentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Calculation of absolute protein–ligand binding free energy from computer simulations

Woo

Roux²

2005

Proc. Natl. Acad. Sci. U.S.A.

634

896

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Free Energy Methods in Ligand Design

Westermaier

Hubbard

2013

De Novo Molecular Design

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Decoding the Rich Biological Properties of Noble Gases: How Well Can We Predict Noble Gas Binding to Diverse Proteins?

et al. 2018

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The chemically inert noble gases display a surprisingly rich spectrum of useful biological properties. Relatively little is known about the molecular mechanisms behind these effects. It is clearly not feasible to conduct large numbers of pharmacological experiments on noble gases to identify activity. Computational studies of the binding of noble gases and proteins can address this paucity of information and provide insight into mechanisms of action. We used bespoke computational grid calculations to predict the positions of energy minima in the interactions of noble gases with diverse proteins. The method was validated by quantifying how well simulations could predict binding positions in 131 diverse protein X-ray structures containing 399 Xe and Kr atoms. We found excellent agreement between calculated and experimental binding positions of noble gases. 94 % of all crystallographic xenon atoms were within 1 Xe van der Waals (vdW) diameter of a predicted binding site, and 97 % lay within 2 vdW diameters. 100 % of crystallographic krypton atoms were within 1 Kr vdW diameter of a predicted binding site. We showed the feasibility of large-scale computational screening of all ≈60 000 unique structures in the Protein Data Bank. This will elucidate biochemical mechanisms by which these novel 'atomic drugs' elicit their valuable biochemical properties and identify new medical uses.

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Modeling protein-small molecule interactions: structure and thermodynamics of noble gases binding in a cavity in mutant phage T4 Lysozyme L99A

Cited by 55 publications

References 35 publications

Calculation of absolute protein–ligand binding free energy from computer simulations

Calculation of absolute protein–ligand binding free energy from computer simulations

Free Energy Methods in Ligand Design

Decoding the Rich Biological Properties of Noble Gases: How Well Can We Predict Noble Gas Binding to Diverse Proteins?

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