version date: 1 December 2006 molecule is rarely a simple sum of its parts and prediction of any molecular property on empirical or calculated fragments has no scientific basis [22]. The Bodor's method computes log P as a function of different calculated molecular properties, like conformations, ionization, hydration, ion- pair formation, keto-enol tautomerism, intramolecular and intermolecular H-bond formation, folding and so forth The fifth log P determination method, based on solvatochromic comparisons, was proposed by Kamlet and coworkers [23] and constitutes, once more, a molecular properties methodology. Log P can be calculated through the following equation log Poct =aV+ bI*+c BH+ daH +e V is a solute volume term, T' is a polarity/polarizability solute term, BH is an independent measure of solute hydrogen-bond acceptor strength, aH the corresponding hydrogen-bond donor strength, while e is the intercept. T*, BH, and aH represent solvatochromic parameters obtained averaging multiple normalized solvent effects on a variety of properties, involving many different types of indicators Several research groups have tried to extend to amino acids the log P calculations, in order to better understand and investigate events like protein folding and biological interactions. However, experimental methods, like chromatography or site-directed mutagenesis, give ambiguous and different results [11]. Generally, each amino acid is characterized by a wide range of hydrophobicity values, thus, deciding and stating which value should correspond to a true measure becomes very difficult and time-consuming In order to obtain rapid and proper estimation of biological molecule hydrophobicity, in 1987 Abraham and Leo extended to common amino acids the fragment method of calculating partition coefficients [10]. Fundamental hydrophobic fragments, obtained from partitioning experiments performed on thousands of compounds, were subsequently reduced to atomic values with inherent bond, ring, chain, branching, and proximity factors. The derived hydrophobic atomic constants and the corresponding SASAs constituted the key parameter of the software HINT(Hydropathic INTeractions), able to directly calculate them for small molecules like ligands, or to obtain them from a residue-based dictionary. The program was thus created with the purpose of rapidly and properly estimating biological interactions such as protein-protein, protein-DNA, and protein- ligand and folding ph Why should we use log P to study and predict recognition and interactions between biological molecules? At least three reasonable answers could be given:(i) log P is essentially an experimental reproducible measurement; (i) partition experiments are low cost and perform relatively rapidly and (iii) log P is directly related to the free energy of binding. In fact, being that hydrophobicity is defined in terms of solubility, log Po/w, and consequently also the hydrophobic atomic constants, <www.iupac.org/publications/cd/medicinalchemistry/>5 molecule is rarely a simple sum of its parts and prediction of any molecular property on empirical or calculated fragments has no scientific basis [22]. The Bodor’s method computes log P as a function of different calculated molecular properties, like conformations, ionization, hydration, ion￾pair formation, keto-enol tautomerism, intramolecular and intermolecular H-bond formation, folding, and so forth. The fifth log P determination method, based on solvatochromic comparisons, was proposed by Kamlet and coworkers [23] and constitutes, once more, a molecular properties methodology. Log P can be calculated through the following equation: log Poct = a V + b π* +c βH + d αH + e V is a solute volume term, π* is a polarity/polarizability solute term, βH is an independent measure of solute hydrogen-bond acceptor strength, αH the corresponding hydrogen-bond donor strength, while e is the intercept. π*, βH, and αH represent solvatochromic parameters obtained averaging multiple normalized solvent effects on a variety of properties, involving many different types of indicators. Several research groups have tried to extend to amino acids the log P calculations, in order to better understand and investigate events like protein folding and biological interactions. However, experimental methods, like chromatography or site-directed mutagenesis, give ambiguous and different results [11]. Generally, each amino acid is characterized by a wide range of hydrophobicity values, thus, deciding and stating which value should correspond to a true measure becomes very difficult and time-consuming. In order to obtain rapid and proper estimation of biological molecule hydrophobicity, in 1987 Abraham and Leo extended to common amino acids the fragment method of calculating partition coefficients [10]. Fundamental hydrophobic fragments, obtained from partitioning experiments performed on thousands of compounds, were subsequently reduced to atomic values with inherent bond, ring, chain, branching, and proximity factors. The derived hydrophobic atomic constants and the corresponding SASAs constituted the key parameter of the software HINT (Hydropathic INTeractions), able to directly calculate them for small molecules like ligands, or to obtain them from a residue-based dictionary. The program was thus created with the purpose of rapidly and properly estimating biological interactions such as protein–protein, protein–DNA, and protein– ligand and folding phenomena. Why should we use log P to study and predict recognition and interactions between biological molecules? At least three reasonable answers could be given: (i) log P is essentially an experimental reproducible measurement; (ii) partition experiments are low cost and perform relatively rapidly; and (iii) log P is directly related to the free energy of binding. In fact, being that hydrophobicity is defined in terms of solubility, log Po/w, and consequently also the hydrophobic atomic constants, <www.iupac.org/publications/cd/medicinal_chemistry/> version date: 1 December 2006