Molecules as complex adaptative systems: Constrained molecular properties and their biochemical significance

The first part of the paper describes molecular structure by considering fo rm (geometrical structure), function (observable properties resulting from interaction with a probe) and fluctuation (dynamics). The fluctuation of fo rm and function generates a number of molecular states, whose ensemble deli neates a property space. This concept is central when examining the mutual interactions of a chemical compound with its molecular environment. Because of these interactions, a chemical compound and its molecular environment m ay form a complex system in its own right, which exhibits emergent properti es (e.g., solubility and lipophilicity) that are non-existent (and meaningl ess) at the level of description of isolated molecules, and which are part of the property space of the compound. The emergence of these properties is accompanied by constraints on the property space of the constituents, and especially of the chemical compound. Some of these constraints are well kno wn, e.g., conformational shifts as seen in induced fit and chameleonic beha viour. Such mutual adaptability between a compound and its environment is a fundamental but insufficiently recognized phenomenon in biochemistry, sinc e it amplifies molecular complementarity and hence molecular recognition. I n the second part of this paper, the results of an exploratory study are re ported which show that contraints on the property space of constituents als o occur when molecules are covalently incorporated into larger compounds. U sing the GRID/VolSurf softwares, we bring evidence that when some amino aci ds become residues in peptides, they experience a modest increase in their polarity and a marked increase in their hydrophobicity (as assessed by thei r polarity field and hydrophobicity field, respectively). The biological an d pharmacological implications of constraints on solutes, ligands and monom ers could inspire new directions of research. (C) 2000 Elsevier Science B.V . All rights reserved.