Hydropathic analysis of the non-covalent interactions between molecular subunits of structurally characterized hemoglobins

Abraham, Donald J.; Kellogg, Glen E.; Holt, Jo M.; Ackers, Gary K.

doi:10.1006/jmbi.1997.1249

Cited by 45 publications

(56 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[22][23][24] In particular, we have presented two previous studies that used high-resolution crystal structures of hemoglobin (Hb) to demonstrate that HINT could accurately estimate changes in free energy for mutant Hb dimer-tetramer assembly. 21,25 Importantly, both of the previous studies clearly showed that not only electrostatic, but also numerous hydrophobic, contacts were responsible for the overall stability of the general Hb tetramer. 21,25 In addition, it was found that the inclusion of crystallographically conserved waters in the analysis of dimer-tetramer assembly was crucial for generating more accurate free-energy estimates in a specific set of mutant deoxy Hb crystal structures.…”

Section: Introductionmentioning

confidence: 93%

“…21 Several studies using HINT have shown that the atom-atom interaction scores generated by this method correlate with binding affinity and/or free energy for a variety of biological systems. [22][23][24] In particular, we have presented two previous studies that used high-resolution crystal structures of hemoglobin (Hb) to demonstrate that HINT could accurately estimate changes in free energy for mutant Hb dimer-tetramer assembly.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Computationally accessible method for estimating free energy changes resulting from site-specific mutations of biomolecules: Systematic model building and structural/hydropathic analysis of deoxy and oxy hemoglobins

et al. 2001

Self Cite

View full text Add to dashboard Cite

Section: Introductionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Computationally accessible method for estimating free energy changes resulting from site-specific mutations of biomolecules: Systematic model building and structural/hydropathic analysis of deoxy and oxy hemoglobins

et al. 2001

Self Cite

View full text Add to dashboard Cite

“…A detailed examination of the interactions between the molecular subunits of hemoglobin has shown that the HINT constants are scalable with ∆G for dimer-dimer assembly with a conversion factor of c.a. one kcal/mol being equivalent to 515 HINT score units [14].…”

Section: Scoring Ligand Binding With Hintmentioning

confidence: 99%

“…In this case the obvious goal would be to reduce the volume of the purple regions by adding the types of functional groups to the ligand that would complement the character of the enzyme binding site. We have calculated similar maps for the subunit-subunit interactions in hemoglobin tetramers [14] and from these we can propose sitedirected mutations that could alter the energetics of the hemoglobin allosteric transition by stabilizing or destabilizing either the R or T endpoint states. HINT is one of the few, if not unique, computational programs that emphasizes the value of understanding and exploiting unfavorable as well as favorable interactions between species.…”

Section: Visualization Of Interactionsmentioning

confidence: 99%

See 1 more Smart Citation

Development of empirical molecular interaction models that incorporate hydrophobicity and hydropathy. The HINT paradigm

Kellogg¹,

Abraham²

1999

Analusis

View full text Add to dashboard Cite

One of the most puzzling aspects of modern computational chemistry is our continuing inability to predict the gross structure of biological macromolecules, especially proteins, from sequence [1]. This is puzzling because we can easily, with convincing accuracy, predict the microstructural features such as bond lengths, angles and conformation of individual sidechains. It is difficult to conceive of analogous situations in other fields of science; more often than not the "macro" is understood and manipulated much more readily than the "micro".There are, of course, a multitude of reasons for this computational impotence. The complexity of biological systems is probably the most obvious. For a single protein we have to consider millions of potential contacts, thousands of degrees of freedom and likely hundreds of individual molecules if water is part of the model. The modeling of water with current methodology is difficult. Where should water be considered as bulk, which is conventionally dismissed by using a non-unity dielectric, and where should individual (ordered and disordered) water molecules be explicitly modeled? It is obvious that water is crucial; not only because of its role as a potent hydrogen bond mediator that supports protein structure, but also because significant entropy arises from displacement and/or movement of water in and out of the system [2]. The lack of adequate representation for entropy, despite the accuracy of the calculations for enthalpy, compromises our understanding of any real biomacromolecular structure or process. Complex dynamics simulations run over significant time frames would seem to be a reasonable response to these problems, but application continues to be expensive; and, even when the starting point of a dynamics simulation is the known crystallographic structure, after significant simulation time periods the final structure often loses much of the biomacromolecule's original secondary and tertiary structure.For some time we have been interested in understanding and exploiting biological structure for a variety of purposes related to developing new disease treatments. The processes of ligand binding, protein-protein associations, protein-DNA associations and etc. are all fundamental to the design of new therapeutic agents. Our approach has been to develop a simple computational model that is based not on force fields, but on an actual experimental free energy measurement -the partition coefficient for octanol/water solubility, logP o/w . This parameter has been used for several decades as a measure of lipid transport that can be often related to the in vivo biological activity of drug candidate molecules [3,4]. LogP o/w has also been shown in many cases to correlate with ligand binding measured in vitro [5,6]. At its simplest level logP o/w and its component fragment and atom terms reveal the type of interactions that the molecule/fragment/atom are able to make with another species. LogP o/w (or fragment/atom constants) less than zero is indicative of a polar (hydrophilic...

show abstract

Complexity in Modeling and Understanding Protonation States: Computational Titration of HIV‐1‐Protease–Inhibitor Complexes

Tripathi

Fornabaio

Spyrakis

et al. 2007

Chemistry & Biodiversity

View full text Add to dashboard Cite

The computational-titration (CT) algorithm based on the 'natural' Hydropathic INTeractions (HINT) force field is described. The HINT software model is an empirical, non-Newtonian force field derived from experimentally measured partition coefficients for solvent transfer between octanol and H(2)O (log P(o/w)). The CT algorithm allows the identification, modeling, and optimization of multiple protonation states of residues and ligand functional groups at the protein-ligand active site. The importance of taking into account pH and ionization states of residues, which strongly affect the process of ligand binding, for correctly predicting binding free energies is discussed. The application of the CT protocol to a set of six cyclic inhibitors in their complexes with HIV-1 protease is presented, and the advance of HINT as a virtual-screening tool is outlined.

show abstract

Hydropathic analysis of the non-covalent interactions between molecular subunits of structurally characterized hemoglobins

Cited by 45 publications

References 37 publications

Computationally accessible method for estimating free energy changes resulting from site-specific mutations of biomolecules: Systematic model building and structural/hydropathic analysis of deoxy and oxy hemoglobins

Computationally accessible method for estimating free energy changes resulting from site-specific mutations of biomolecules: Systematic model building and structural/hydropathic analysis of deoxy and oxy hemoglobins

Development of empirical molecular interaction models that incorporate hydrophobicity and hydropathy. The HINT paradigm

Complexity in Modeling and Understanding Protonation States: Computational Titration of HIV‐1‐Protease–Inhibitor Complexes

Contact Info

Product

Resources

About