Evolutionary molecular modeling

Many alkaloids fall into the class of spedflc modulators and have been modified during evolution in such a way that they mimic endogenous ligands, hormones, or substrates [1,3,18,19]. We have termed this selection process evolutionary molecular modeling [12,13,19,23]. Many alkaloids are strong neurotoxins that were selected for defense against animals [2,3,19]. Table 1.1 summarizes the potential neuronal targets that can be affected by alkaloids. Extensive reviews on this topic have been published [2,3,19]. 

A. Bloactlve natural product ("Evolutionary Molecular Modeling")... 

Fig. (8). Comparison between. .evolutionary molecular modeling" (A) and "chemical molecular modeling" (B),...

The molecular diversity and multipurpose biological effects of alkaloids has been postulated as the result of evolutionary molecular modeling [69], The data presented in this chapter supports such hypothesis but without restrictions in terms of chemical class as long as the molecule being considered is involved in the defensive strategy of a plant. 

Research on biological evolution entered the realm of science in the 19th century with the centennial publications by Charles Darwin and Gregor Mendel. Molecular models for evolution under controlled conditions became available only in the second half of the twentieth century after the initiation of molecular biology. This chapter presents an account of the origins of molecular evolution and develops the concepts that have led to successful applications in the evolutionary design of biopolymers with predefined properties and functions. 

Table IV also lists the structure analyses of three bacterial cytochromes. Logically these should be delayed to the second half of the chapter, but the results have had such an important influence on thinking about oxidation-reduction mechanisms that their discussion here is mandatory. A key structure study from an evolutionary standpoint was that of R. rvhrum by Salemme, Kraut, and colleagues at the University of California, San Diego (30,31). That study established in one stroke that the eukaryotic cytochrome fold also extended to a bacterial cytochrome and included the cytochromes of photosynthesis as well as respiration. The fact that this structural homology had been predicted on the basis of amino acid sequence comparisons (32) did not lessen the excitement of seeing direct confirmation from the molecular model. Only one of three possible conclusions can be drawn ...

A second is the study of three dimensional molecular models, to permit one to make predictions about the effects of particular substitutions and, on the basis of the transitions allowed by the genetic code, to exclude some substituents, as incompatible with the preservation of molecular function, from the list of possible evolutionary intermediates. 

Approaches to structure prediction using different flavors of secondary structure constraints have been recently reported. This renewed interest in the use of secondary structure information as a way of reducing conformational space when building molecular models is the result of the recent improvement in accuracy of secondary structure prediction methods due to the introduction of evolutionary information. 

The model of evolutionary dynamics has been applied to interpret the experimental data on molecular evolution and it was implemented for computer simulations (Huynen et al., 1996 Fontana and Schuster, 1998). The computer simulations allows one to follow the optimization process in full detail at the molecular level. 

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