Hydrophobicity Revisited: a Molecular Story

Abstract

In a previous paper we have introduced a new hydrophobicity proclivity scale and justified its superior performance characteristics, particularly in the context of a scale for protein alignments, but also for its strong correlation with many other amino-acid physico-chemical properties. Within that paper, we calculated a corrected free energy of residue burial of each amino-acid in folded proteins from a linear regression of amino-acid free energy of transfer from water to n-Octanol (F&P octanol scale dGow, Y axis) and our Hydrophobicity Proclivity Scale<br>(HPS, X axis). In this present paper we pursue the latter general findings in more detail by considering the relationship of hydrophobicity and other physico-amino-<br>acid scales with the molecular geometry of amino-acids and secondary group structure/surface chemistry, with a concommitant discussion of the dimensions/geometry<br>of the caveties that amino-acids make in water. We identify a series of molecular physico-chemical properties that uniquely define the natural selection and geometry of the 20 natural amino-acids. We use the corrected free energy of amino-acid burials in proteins (Y axis) and a multiple linear regression to identify the AA molecular physico-chemical properties (X1, X2, ...) that explain the energetics of amino-<br>acid water contacts in an unfolded protein state to that of the folded protein state by modeling these two states as a solvent-solvent transfer, thus, providing a thermodynamical model for the initial stages of protein folding. Between our previous paper and the current paper we can greatly simplify and reduce the very large number of amino-acid scales in the literature to a small number of amino-acid property scales. Finally, we explore the numerical relationship between the structure of the genetic code and molecular physico-chemical properties of AA’s that in turn can be related directly to hydrophobicity. We validate and explain our novel models we describe herein with extensive data from the literature.<br>

A hydrophobic proclivity index for protein alignments

“…When the relationships in Figure 3- Figure 5 (with supporting literature) are taken together, the hydrophobicity potential driving protein folding is suggested to be the traditional solvent-solvent partitioning model of protein folding where amino-acids partition between aqueous exposure and burial within the hydrophobic core of folded proteins. We believe that this traditional model of the primary driving force for globular protein folding is apt, but needs some updates and modifications that we develop in detail within the forthcoming manuscript -Hydrophobicity revisited: A Molecular Story 34 . We are suggesting in the present manuscript that aqueous clathrates form about the hydrophobic areas of amino-acids in an unfolded state (a structural feature) and hydrophobic surface area on folded proteins possess a surface tension like a gas bubble in water.…”