Data processing: measuring – calibrating – or testing – Measurement system in a specific environment – Biological or biochemical
Reexamination Certificate
2000-01-24
2003-05-06
Brusca, John S. (Department: 1631)
Data processing: measuring, calibrating, or testing
Measurement system in a specific environment
Biological or biochemical
C530S300000
Reexamination Certificate
active
06560542
ABSTRACT:
FIELD OF THE INVENTION
The invention relates generally to peptide molecules and to methods of designing peptides or peptide-like molecules. More particularly, the invention relates to novel, short peptides or peptide-like molecules which have a high probability of binding to and/or otherwise modulating the function of polypeptides or proteins, and to methods for designing such peptides or peptide-like molecules.
BACKGROUND OF THE INVENTION
All protein sequences, whether peptides, polypeptides, or proteins, are composed of a linear sequence of amino acids joined by peptide bonds. There are twenty naturally occurring amino acids, each bearing a chemically unique side chain. Determinants of polypeptide interactions, such as those between peptide segments in protein folding or between protein monomers, are encoded in the one-dimensional sequence of these twenty amino acid side chains. For purposes of this application, “peptides” are generally considered to be amino acid polymers of not more than 25 amino acids in length; “polypeptides” are generally considered to be polymers of between 25 and 50 amino acids; and “proteins” are generally considered to be polymers containing more than 50 amino acids. One of ordinary skill in the art would appreciate that some overlap among these ranges is expected, and minor deviations from these ranges does not in any way diminish the scope of the invention. The “naturally occurring amino acids” are those that are encoded for in the genetic code, and which are generally considered to be those found in all living species to date.
Net differences in the cumulative energetic contributions of several types of weak bonding mechanisms, totaling as little as &Dgr;G=5-10 kcal/mol, determine selection and stabilization among conformations observed in protein folding, protein-protein interactions and the initial phases of substrate-enzyme and ligand-membrane receptor association. In particular, the minimization of &Dgr;G through the formation of four general types of weak bonding mechanisms between amino acid side chains, in the range of &Dgr;G≅2-7 kcal/mol, determines the arrangement of protein sequences in three-dimensional space, as well as the relative orientations of protein chain aggregates, in aqueous environments and at physiological temperatures. The thermal instability of the conformations supported by these low &Dgr;G, reversible, weak-bonding mechanisms permits uncatalyzed, fast searches of configuration space for functionally optimal cooperative arrangements within and between polypeptide and protein monomers. The variety of weak bond capacities afforded by amino acid side chains determines the range of the amino acid sequences' physicochemical property transformations listed in this invention.
The weak bonds ordering polypeptides and proteins in three-dimensional space include hydrogen bonds, such as the main chain amino acid carbonyl and imino groups, which configure the right-turning &agr;-helices and the parallel and antiparallel &bgr;-sheets. They also include the hydrogen and ionic bonds between amino acid side chains, such as the hydroxyl groups of serine and threonine, the acidic carboxyl groups of aspartate and glutamate, and the basic groups of lysine and arginine. In addition to being distinct with respect to the chemical group, these weak hydrogen and ionic bonding influences are also directionally specific, with bonding angles greater than 30° reducing their influence to negligible levels.
A third but nondirectional type of weak bonding interaction, induced by fluctuating charges within a distance of 1-3 Å, is called van der Waal forces. These interactions vary with the size and the extent of mutual geometric fit, but are in the range of 1-2 kcal/mol. These forces are barely greater than those due to the heat of molecular motion at room temperature (&Dgr;G≅0.6-1.0 kcal/mol). However, in the specific cases of some antibody/antigen interactions and MHC protein/peptide interactions, which involve water-releasing tight fits between corresponding moieties in suitably shaped binding pockets, the &Dgr;Gs associated with van der Waals interactions have been estimated to be as high as 30 kcal/mol.
A fourth weak bonding mechanism, and the most energetically dominant force on three-dimensional polypeptide structure and protein-protein interactions, is termed the hydrophobic effect. The hydrophobic effect arises from the much stronger attraction that water molecules have for each other than for hydrocarbon groups or molecules. Each tetrahedrally-coordinated water molecule participates in strong, hydrogen-bonded, dipole/dipole interactions with other water molecules that are manifested in the properties of water such as its high surface tension, high latent heat and high boiling point. These physicochemical features of water molecules afford a large variety of possible atomic arrangements of water (as seen in the large number of different ice types) that in turn permit maximizing the entropy and minimizing the free energy of the aqueous solution. Spatially distributed (nondirectional) deformations in these hydrogen-bonded arrangements of water result from the intrusion of nonpolar, hydrophobic solutes. The introduction of such molecules into an aqueous solution results in the formation of volume-expanding hydration shells composed of hydrogen-bonded cages of multiple molecular layers of water (“clathrate structures”) around these molecules, in a process called “hydrophobic hydration”. In aqueous solutions, such deformations in water structure are energetically unfavored. For example, the side chains of alanine, valine, leucine and isoleucine are without effective dipole moments, and therefore cannot participate in charge-mediated or hydrogen-bonding interactions with water. As a result, these side chains intrude into the aqueous solvent and disrupt the ordered structure of the aqueous solvent, resulting in an increase in the overall &Dgr;G. Amino acids with polar but uncharged side chains, such as serine and threonine, may hydrogen bond with a molecule of water, but otherwise undergo the same kind of hydrophobic hydration as the non-polar side chains. In the case of amino acids with side chains containing charged groups, such as glutamate or lysine, the electrostatic fields associated with these side groups are screened by water molecules, such that in an aqueous solution hydrophobic hydration is still a prominent characteristic of these amino acids as well. The nonlocal, cooperative interactions of the hydrogen bonds of the aqueous solvent surrounding these amino acids drive the in-line, surface-minimizing attraction between the coherent hydrophobic-phase patches of amino acid side chains, thereby maximizing the entropy, and minimizing the free energy, of the overall aqueous solution.
The importance of the sequential arrangements of amino acid side chain hydrophobicities in the determination of peptide and protein secondary structures has been established knowledge in protein biology for many decades. The ready availability of water for compensatory weak bonding implies that relatively small changes in &Dgr;G occur when internal peptide backbone-related, carbonyl-imino hydrogen bonding or side chain polar groups are not satisfied. This-contrasts with the much greater alteration in &Dgr;G associated with loss of internal hydrophobic bonding, which cannot be compensated by the hydrophobically disrupted, aqueous environment. Minimization of hydrophobic free energy, &Dgr;G
hp
, by water interface-reducing aggregation of nonpolar, hydrophobic amino acid side chain groups adds to the &Dgr;G of binding that can, collectively, be orders of magnitude larger than that predicted by van der Waals theory. Mutually attractive forces mediated by hydrophobic surface minimization have been measured by atomic force spectroscopy to extend to as great a distance as 60 Å, the length scale of synaptic gaps. These attractive forces decay less than exponentially with distance. The contribution to the energy of stabilization of the th
Mandell Arnold J.
Selz Karen A.
Shlesinger Michael F.
Brusca John S.
Howrey Simon Arnold & White
The Cielo Institute
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