Molecular Evolutionary Models in Drug Discovery

book

Preface

Juan Bueno, Bogotá, Colombia

Biology on the planet has evolved from chance and necessity, just as Jacques Monod (1910–76) theorized. In this order of ideas, chance is represented by environmental challenges that exert stress on the biological system so that it initiates phenotypic adaptations, which when made functional become heritable and are transmitted to the following generations. Necessity is represented in the search of the living being to continue to function by using nutrients for energy, reproducing, and defending its space. To achieve functionality by virtue of the game of chance and the need that has shaped our biosphere, biological systems enter into communication and association so that in symbiosis they acquire fitness and the ability to transcend from an RNA world to an open biological system in constant exchange. And in this way, by virtue of association, communication, and mutualism, the biological entity holobiont conformed by a host and its symbionts emerges as an evolutionary model that allows biological systems to acquire autopoiesis (produce themselves) and autocatakinetics (organize themselves to themselves) with the consequent ability to share the entropy and configure metabolic networks for this purpose. On the other hand, the holobiont communicates with other holobionts in its ecosystem, configuring a network known as the meta-holobiont. This meta-holobiont is a superorganism in its communication process and acquires molecular evolution able to give greater capacity of fitness to the biological system and consequently of adaptation. Thus by assuming the human being as a holobiont, a biological system in constant ecoevolution and search for adaptation, it is possible to achieve another vision of medicine based on the complex systems with which a functional model can be developed to design new symbiotic medications. This symbiotic therapy is defined as reestablishment of ecosystemic equilibrium for treatment of the human holobiont. This reestablishment seeks to avoid tissue invasion and uncontrolled growth to achieve a correct thermodynamic homeostasis. This approach is also based on the quaternity of the exchange in an open biological system that consists of:

1.interaction

2.communication

3.transformation

4.evolution

Likewise, the characteristics of a symbiotic medication administered alone or in synergistic formulation are:

1.Allows and regulates phenotypic adaptations within the holobiont

2.Restores metabolic networks that allow energy exchange within the holobiont

3.Helps maintain and restore the thermodynamic equilibrium in the sharing of entropy

4.Maintains mutualistic interactions between the host and its symbionts

5.Induces proliferation of beneficial microbial species for the microbiome

6.Restores the homeosis between microbiome and host

7.Controls pathogenic microorganisms mediated by stimulation of probiotic microbial consortia

8.Does not present antimicrobial activity on the microbiome

9.Does not present toxicity against the symbiotic holobiont as a whole

Therefore in the context of personalized medicine, the criterion of the 4Ps (predictive, preventive, participatory, and personalized) should include a new factor that represents the evolution of the biological system, which we call the fifth P, pliability. We include pliability in order to complete the missing information as well as its correlations for the design and development of pharmacological innovations.

The main objective of this book is to integrate evolution as a biological phenomenon that has shaped the biosphere to the search and development of therapeutic innovations for use in medicine, agriculture, and industry. But for this we must connect the holobiont and its symbionts as the functional biological unit in association and communication that has emerged as a strategy to reach thermodynamic equilibrium and to that extent continue the metabolic flow of energy in the system.

Chapter 1

Molecular evolution: The origins of interaction

Abstract

Molecular evolution involves the process by which changes occur through the generations of cellular molecules such as DNA, RNA, and proteins. The origin of these changes is determined from the origin of life by the connection networks established by living beings. In a similar way, these modifications are due to the adaptation that organisms make to their environment, which is initially phenotypic, in preparation for the genotypic type alterations that characterize the evolutionary processes. It is when accumulating innovations that biological systems acquire greater complexity, which directs towards the specialization and the conformation of multicellular organisms. Likewise, these adaptive processes finally achieve that the protocells gain their properties of replication and self-sustainability due to the development of primary metabolic processes regulated by secondary metabolites. Equally, these secondary metabolites, as they obtain increasing biological activity, become a determining factor in coevolution and adaptation within ecosystems. This is how these processes of evolution, developed in large periods of biological interaction, can be the basis for the creation of a new model of biotechnological applications that use metabolic networks and their connections as a source of innovation. Finally, the objective of this chapter is to open the introduction to the knowledge and central theme of this book, on how to understand evolution and its concepts for the study and application of new approaches that can boost the development of industrial biochemistry and biomedicine.

Keywords

Evolution; Biological molecules; Secondary metabolism; Holobiont; Biocenosis

Acknowledgments

The author wants to thank P.S. Bird for his accompaniment and wise advice in ecosystem niches during the writing of this chapter.

It was in these circumstances… in which he analyzed Don Quixote’s dilemma of whether to follow the path of arms (praxis, action) or the path of letters (poiesis, creation, production), I understood for the first time the power of the word poiesis and invented the word that we needed: autopoiesis. This was a word without a history, a word that could directly mean what takes place in the dynamics of the autonomy proper to living systems.

Humberto Maturana (1928–) and Francisco Varela (1946–2001)

Only love expands intelligence. To live in love is to accept the other and the conditions of his existence as a source of richness, not as opposition, restriction or limitation.

Humberto Maturana (1928–)

1.1 Introduction

The study of the evolution of biological molecules itself is nothing other than the evaluation of quasicrystals or aperiodic crystals (Maciá, 2005). This aperiodic order (orderly but without symmetry) has been the key to diversity and evolution since the appearance of the first molecules that had the capacity to self-replicate and with the ability to obtain memory patterns for future living systems (Jacobs & Frenkel, 2016; Zenil, 2013). Thus, prebiotic chemistry, like all forms, has physical laws that determine it, such as the state of the matter (Cleaves, 2018; Spitzer, Pielak, & Poolman, 2015), but the set of these laws that allow the origin of life from the interaction of molecules requires the nonlinearity of the dynamic process as well as the chaos that chance induces (Detrain & Deneubourg, 2006; Longo, Montévil, & Kauffman, 2012; Strogatz, 2018). That is why starting from molecular evolution as a primordial that is nourished by the interaction and communication between biological systems and their environment is probably the gateway to a set of foundations that will regulate a future series of biotechnological applications (Barge et al., 2017; Wagner & Rosen, 2014). In this way, the game of biological macromolecules is established through interaction and communication that ultimately achieves the storage of useful information (Massey & Mishra, 2018).

This information on complex biological systems will determine the appearance of replicators that will initiate adaptive mutation processes when they come into contact with the environment and its changes (Ma'ayan, 2017; Melkikh, 2014). This is how molecular evolution will modulate phenotypic changes in different species as a means to achieve this adaptation (Chevin & Beckerman, 2012; Harms & Thornton, 2013). These challenges are also used as a means of molecular innovation that increases chemical diversity and resilience capacity to assume the external pressure that will allow evolutionary success (López-Maury, Marguerat, & Bähler, 2008). Finally, the macromolecules were diversified into the correspondence between the information represented by the genome and the functionality represented by the genotype both in their constant exchange of the environment (Sharov, 2014). Additionally, the thermodynamic flow that establishes the self-sustainability of the molecular evolution process must be taken into account to elucidate fluxomics in the production of metabolites, both primary and secondary (Kleidon, Malhi, & Cox, 2010). This is how the methods of evolutionary engineering appear as a consilient platform to develop chemical diversity of the capacity to use the adaptive potential for the species (Arnold, 2015; Shepelin, Hansen, Lennen, Luo, & Herrgård, 2018); all this comes from the study of social interactions between living organisms, which evolved from the exercise in communication as a means of survival (Flemming et al., 2016). The objective of this chapter will be to analyze the physical, chemical, and biological systems that make up the molecular interaction and that constitute a factor of evolution whose foundations will be applied in evolutionary engineering models.

1.2 Aperiodic crystals and biological molecules

The organization of complex biological systems is bound to the laws of physics, in particular to quantum mechanics, which establishes the capacity for innovation and evolution of species in thermodynamic flows (Katsnelson, Wolf, & Koonin, 2018). In this way, the primordial/prebiotic soup composed of aperiodic crystals (conformed molecules in a nonperiodic ordered structure) capable of self-replicating were fundamental for the appearance of the first symbiotic cell or protobiont that came into interaction (Fig. 1) (Longo, Montévil, Sonnenschein, & Soto, 2015). Also, the physical and chemical properties of these molecules predispose to their micro-scale organization what preprogrammed their use in different cellular functions in the guise of an evolutionary geometry that lost periodicity or symmetry when they are represented in a three-dimensional space like regular crystals (Fig. 2) (Jorgenson, Mohammed, Agrawal, & Schulman, 2017; Murr, 2015). Likewise, these structures capable of carrying information are the link between an abiotic world and the emergence of life (Varn & Crutchfield, 2016; Wills, 2016). Equally, it is very important to take into account the emergence of autocatalytic sets, in which the symbiotic protobiont emerges from a group of molecules that formed a cooperative network that self-replicated together (Walker, 2017). Additionally, the autocatalytic network will be established as it acquires a state of homeostatic organization that allows it to configure a complex biosystem (Eskov, Filatova, Eskov, & Gavrilenko, 2017); in other words, it becomes self-sustaining and by compartmentalizing, it acquires the characteristics of a protocell (Hordijk, Naylor, Krasnogor, & Fellermann, 2018). Consequently, in the present living cells, the fact of being a nonperiodic molecular structure allows the interaction and the union of lengths, sizes, and forms into irregular configuration, as it is in those that the biological processes are developed (Polesskaya et al., 2018).

Fig. 1 Evolution of life from prebiotic soup until the protocell origin and multicellular organization.

Fig. 2 Aperiodic structure of quasicrystal based on a Penrose tiling.

It is also important to note that this prebiotic chemistry that subsequently accumulated in vesicles required three fundamental processes: integration with the vesicle to prevent its degradation, stabilization of the structure of the vesicle in a symbiotic model, and finally, the development of a function in the role as protocell, all as part of the same life that is governed by physical-chemical laws (Mayer, Schreiber,& Dávila, 2015, 2017). In order for these ideas to acquire their function, the protocell established a metabolic network perpetuated in genetic information consigned to aperiodic crystal structures (De Tiège, 2017). Thus, from this abiotic world, through interaction, the different hierarchies of biological systems were reached, from a molecular level to a population level (Tëmkin & Eldredge, 2015). In this way, a crucial factor of the interactions within the protocols is the establishment of hyper cycles, in which self-replicating molecules such as RNA and DNA constitute cyclic connections that are autocatalytic (Sardanyés, Lázaro, Guillamon, & Fontich, 2017). It is in these hyper cycles where the interactions between the proteins reached self-sustaining processes of replication and communication allowed the origin of life (Andras & Andras, 2005); everything from a primordial soup of aperiodic crystals. But although Erwin Scrödinger suggested that these crystals would have the capacity to carry information (in his words, a Morse code) that leads to survival through communication (Zwart, 2018), it is necessary to discuss a little more as each protocol entered into symbiosis with its neighbors.

1.3 Cell-to-cell communication

Our microbial ancestors developed communication systems initially to perceive and control low population density of different conditions of environmental nutrients; the best known is called quorum sensing, which is an early-onset mechanism in bacteria (Lerat & Moran, 2004; Schluter, Schoech, Foster, & Mitri, 2016). The system of quorum sensing regulates the cooperation of microbial cells in response to external pH and stress as factors, inducing different functions such as replication, gene exchange, and formation of biofilm associations (Moreno-Gámez et al., 2017). Likewise, as the system becomes redundant due to the development of several molecular signaling pathways, it acquires complexity, forming information networks within cell communities (Even-Tov et al., 2016). Finally, these forms of communication determined the processes that led to endosymbiotic relationships between α-proteobacteria and the archaean host, which led to the appearance of mitochondria as a metabolic organelle (Chandel, 2015). This fusion, which was derived from the role of the activation of quorum sensing during the increase in the population density and the decrease of nutrients, was able to promote survival and adaptation during shortage of energy resources (Picard & Burelle, 2012). For that reason, the evolutionary adaptations of the signaling system focus on the intracellular distribution of carbon and energy resources (Wu et al., 2016). Additionally, as these self-inductors produced in the quorum sensing achieved the adaptation for survival, they also had a primordial role in the establishment of a symbiotic network of interaction with other microorganisms in constant evolution of the constitution of structured communities with ecosystem functions as the form of a biofilm (Hansen, Rainey, Haagensen, & Molin, 2007). This formation favored the primordial microorganisms to achieve an adaptive diversification into the ecosystem niche that confers cooperation and exchange with information on different microbial populations (Steenackers, Parijs, Foster, & Vanderleyden, 2016).

1.4 Biofilm as an evolutionary niche

In microbial ecology, the adaptation and survival of different species was a fundamental factor of establishing the evolutionary process that developed terrestrial biodiversity (Van Der Heijden, Bardgett, & Van Straalen, 2008), also constituting a terrestrial microbiome in constant exchange (Fröhlich-Nowoisky et al., 2016). In this way, microorganisms from the origin of life have established themselves as the greatest promoters of biodiversity, due to the ability to perform symbiosis with other organisms in a constant exchange of information within a hologenome that groups the coded information of both the host and the microbiota with which it is in contact (Rosenberg & Zilber-Rosenberg, 2018; Zilber-Rosenberg & Rosenberg, 2008). In this conformation of the symbiotic holobionts (microbial communities and their host both plant and animal), the biofilm has played a fundamental role in the establishment of a microbial ecosystem that can interact as a whole with its symbiont (Doolittle & Booth, 2017). This is how, when conceiving modern living beings as multi organismal entities, it is possible to determine the influence of microorganisms on the physiology, metabolism and molecular signaling inside the host (Douglas, 2018). In addition, Bordenstein and Theis (2015) had postulated the basic principles of holobionts and hologenomes that should be taken into consideration when approaching these complex systems as a driver of molecular evolution, such