Toward the semiquantitative estimation of binding constants. Guides for peptide-peptide binding in aqueous solution

Williams, Dudley H.; Cox, Jonathan P.L.; Doig, Andrew J.; Gardner, Mark; Gerhard, Ute; Kaye, Perry T.; Lal, Allick R.; Nicholls, Ian A.; Salter, Colin J.; Mitchell, Robert E.

doi:10.1021/ja00018a047

Cited by 202 publications

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“…-72 kJ mohl1 (1,6). Since the dimer is certainly not rigid, and will retain some residual motion, AGt+r appears to be overestimated by the above arithmetic.…”

Section: Dimerization Of Vancomycin Group Antibioticsmentioning

confidence: 98%

“…We have recently (1) built upon earlier work of Page and Jencks (2) and Jencks (3) in utilizing an equation which divides the observed free energy of binding (AG, kJ mol') for a bimolecular association in aqueous solution (A + B A-B) into several components: AG = AGt+r + AGr + AGh + >AGp + AGVdW + AGcOn. [1] AGvdW is the difference in the free energy of van der Waals interactions between the binding surfaces of A and B to each other and to solvent, and AGconf is the difference in the conformational free energies between free and bound states.…”

mentioning

confidence: 99%

“…[1] AGvdW is the difference in the free energy of van der Waals interactions between the binding surfaces of A and B to each other and to solvent, and AGconf is the difference in the conformational free energies between free and bound states. For the case where the binding surfaces ofA and B have good complementarity, and where A and B can bind in the complex close to the conformational energy minima found for the components in free solution, we approximate the terms AGVdw and AGconf to zero (1). In the simpler equation which is then applicable (Eq.…”

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confidence: 99%

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Toward an estimation of binding constants in aqueous solution: studies of associations of vancomycin group antibiotics.

Williams¹,

Searle²,

Mackay³

et al. 1993

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

159

108

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An approach toward the estimation of binding constants for organic molecules in aqueous solution is presented, based upon a partitioning of the free energy of binding. Consideration is given to polar and hydrophobic contributions and to the entropic cost of rotor restrictions and bimolecular associations. Several parameters (derived from an analysis of entropy changes upon the melting of crystals and from the binding of cell wafl peptide analogues to the antibiotic ristocetin A) which may be useful guides to a crude understanding ofbinding phenomena are presented: (i) amide-amide hydrogen bond strengths of -(1 to 7) ± 2 kJ-mol-1, (ii) a hydrophobic effect of -0.2 ± 0.05 kJUmol-l.A2 of hydrocarbon removed from exposure to water in the binding process, and (ii) free energy costs for rotor restrictions of 3.5-5.0 kJ mol'1. The validity of the parameters for hydrogen bond strengths is dependent on the validity of the other two parameters. The phenomenon of entropy/enthalpy compensation is considered, with the conclusion that enthalpic barriers to dissociations will result in larger losses in translational and rotational entropy in the association step. The dimerization of some vancomycin group antibiotics is strongly exothermic (-36 to -51 kJ-mol'1) and is promoted by a factor of 50-100 by a disaccharide attached to ring 4 (in vancomycin and eremomycin) and by a factor of ca. 1000 by an amino-sugar attached to the benzylic position of ring 6 in eremomycin. The dimerization process (which, as required for an exothermic association, appears to be costiy in entropy) may be relevant to the mode of action of the antibiotics.We have recently (1) built upon earlier work of Page and Jencks (2) and Jencks (3) in utilizing an equation which divides the observed free energy of binding (AG, kJ mol') for a bimolecular association in aqueous solution (A + B A-B) into several components: AG = AGt+r + AGr + AGh + >AGp + AGVdW + AGcOn. [1] AGvdW is the difference in the free energy of van [2]In using this approach, we recognize that the derived parameters will be approximate only and may indeed vary from one environment to another (4). The analysis may be additionally complicated by cooperativity. It nevertheless seems worthwhile to attempt a semiquantitative approach even if only to give rough estimates of these parameters and to underscore any problems which the analysis may uncover.For an intramolecular association, the term AGt+r disappears and, in the idealized equation (Eq. 2), only three terms then remain. In intramolecular cases of complex interactions, such as protein folding, there will be conformational strain in the associated (folded) state and probably also better van der Waals packing in the folded state. In these cases, AGconf and AG~dw are, respectively, unfavorable and favorable toward folding, and the free energy of association is thus partitioned into a total of five terms (cf. Eq. 1). Derivation of Some Free Energy ContributionsIn an initial application of the method (1, 5) the binding of mono-and d...

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“…-72 kJ mohl1 (1,6). Since the dimer is certainly not rigid, and will retain some residual motion, AGt+r appears to be overestimated by the above arithmetic.…”

Section: Dimerization Of Vancomycin Group Antibioticsmentioning

confidence: 98%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Toward an estimation of binding constants in aqueous solution: studies of associations of vancomycin group antibiotics.

Williams¹,

Searle²,

Mackay³

et al. 1993

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

159

108

View full text Add to dashboard Cite

show abstract

“…This product (I.a) also features in some QSAR expressions, such as those for melatonin analogues [44], thus indicating that dispersion forces could be involved in melatonin receptor binding. Furthermore, it is possible to make a reasonable estimate of the binding affinity between melatonin and its receptor based on the Williams et al [45] expression for the various components likely to be involved, with hydrogen bonding (see Table 3 for some typical values) making a significant contribution [46]. In contrast, a derivation for the binding energy of camphor to cytochrome P450 cam indicates that hydrophobic forces (desolvation) make the largest contribution [34].…”

Section: Appendix a Derivation Of Solvation And Desolvation Energiesmentioning

confidence: 99%

Molecular Binding Interactions: Their Estimation and Rationalization in QSARs in Terms of Theoretically Derived Parameters

Lewis

Broughton

2002

The Scientific World JOURNAL

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An extensive survey of molecular binding interactions and parameters used in QSARs is reported, which includes consideration of lipophilicity and the derivation of Linear Free Energy Relationships associated with drug-receptor binding, together with an overview of the various contributions to binding energy. The lipophilic parameter, log P, and its relevance to desolvation energy is outlined and explanation of the parameters derived from electronic structure calculation is provided, leading into a summary of molecular dynamics simulations. KEY WORDS: drug-receptor binding interactions, quantitative structure-activity relationships (QSARs)

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“…Molecular dynamics simulations including the explicit treatment of solvent molecules have encountered a number of striking successes (see, e.g., Bash et al, 1987;McCammon, 1987;Beveridge & DiCapua, 1989;Straatsma & McCammon, 1991;Miyamoto & Kollman, 1993;Kollman, 1993Kollman, , 1994; however, the need to sample a large ensemble of conformational states places severe computational demands on this approach. At the other extreme, a variety of empirical methods have also been developed to estimate binding free energies (see, e.g., Andrews et al, 1984;Williams et al, 1991Williams et al, , 1993Bohm, 1994). These methods, which, for example, assign a free energy value to each hydrogen bond, salt bridge, and buried nonpolar area, provide extremely useful qualitative tools.…”

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confidence: 99%

On the calculation of binding free energies using continuum methods: Application to MHC class I protein‐peptide interactions

1997

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This paper describes a methodology to calculate the binding free energy (AG) of a protein-ligand complex using a continuum model of the solvent. A formal thermodynamic cycle is used to decompose the binding free energy into electrostatic and non-electrostatic contributions. In this cycle, the reactants are discharged in water, associated as purely nonpolar entities, and the final complex is then recharged. The total electrostatic free energies of the protein, the ligand, and the complex in water are calculated with the finite difference Poisson-Boltzmann (FDPB) method. The nonpolar (hydrophobic) binding free energy is calculated using a free energy-surface area relationship, with a single alkane/water surface tension coefficient (yaw). The loss in backbone and side-chain configurational entropy upon binding is estimated and added to the electrostatic and the nonpolar components of AG. The methodology is applied to the binding of the murine MHC class I protein H-2Kb with three distinct peptides, and to the human MHC class I protein HLA-A2 in complex with five different peptides. Despite significant differences in the amino acid sequences of the different peptides, the experimental binding free energy differences (AAGexp) are quite small (<0.3 and <2.7 kcal/mol for the H-2Kb and HLA-A2 complexes, respectively). For each protein, the calculations are successful in reproducing a fairly small range of values for AAGCalc (<4.4 and <5.2 kcal/mol, respectively) although the relative peptide binding affinities of H-2Kb and HLA-A2 are not reproduced. For all protein-peptide complexes that were treated, it was found that electrostatic interactions oppose binding whereas nonpolar interactions drive complex formation. The two types of interactions appear to be correlated in that larger nonpolar contributions to binding are generally opposed by increased electrostatic contributions favoring dissociation. The factors that drive the binding of peptides to MHC proteins are discussed in light of our results. and AGs,,lv); AG.,, nonpolar (hydrophobic) contribution to binding; AG,,,,,, change in conformational free energy of both the receptor and the ligand upon binding; AS,, and AS,, loss of configurational entropy due to the freezing of backbone and side-chain torsional angles upon binding; A&, loss of translational and rotational degrees of freedom upon binding; A, solvent-accessible surface area; yaw, microscopic surface tension associated with the transfer of alkane from liquid alkane to water: E,, dielectric constant of water; 6 , dielectric constant of macromolecular interior. KeywordsThe accurate calculation of ligand-protein binding free energies is a difficult problem for which no general solution has been forthcoming. Molecular dynamics simulations including the explicit treatment of solvent molecules have encountered a number of striking successes (see, e.g., Bash et al

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Toward the semiquantitative estimation of binding constants. Guides for peptide-peptide binding in aqueous solution

Cited by 202 publications

References 1 publication

Toward an estimation of binding constants in aqueous solution: studies of associations of vancomycin group antibiotics.

Toward an estimation of binding constants in aqueous solution: studies of associations of vancomycin group antibiotics.

Molecular Binding Interactions: Their Estimation and Rationalization in QSARs in Terms of Theoretically Derived Parameters

On the calculation of binding free energies using continuum methods: Application to MHC class I protein‐peptide interactions

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