Directed enzyme evolution: climbing fitness peaks one amino acid at a time

Directed evolution can generate a remarkable range of new enzyme properties. Alternate substrate specificities and reaction selectivities are readily accessible in enzymes from families that are naturally functionally diverse. Activities on new substrates can be obtained by improving variants with broadened specificities or by step-wise evolution through a sequence of more and more challenging substrates. Evolution of highly specific enzymes has been demonstrated, even with positive selection alone. It is apparent that many solutions exist for any given problem, and there are often many paths that lead uphill, one step at a time

Evolutionary Multi-Objective Design of SARS-CoV-2 Protease Inhibitor Candidates

Computational drug design based on artificial intelligence is an emerging research area. At the time of writing this paper, the world suffers from an outbreak of the coronavirus SARS-CoV-2. A promising way to stop the virus replication is via protease inhibition. We propose an evolutionary multi-objective algorithm (EMOA) to design potential protease inhibitors for SARS-CoV-2's main protease. Based on the SELFIES representation the EMOA maximizes the binding of candidate ligands to the protein using the docking tool QuickVina 2, while at the same time taking into account further objectives like drug-likeliness or the fulfillment of filter constraints. The experimental part analyzes the evolutionary process and discusses the inhibitor candidates.Comment: 15 pages, 7 figures, submitted to PPSN 202

Metabolomics methods for the synthetic biology of secondary metabolism

Many microbial secondary metabolites are of high biotechnological value for medicine, agriculture, and the food industry. Bacterial genome mining has revealed numerous novel secondary metabolite biosynthetic gene clusters, which encode the potential to synthesize a large diversity of compounds that have never been observed before. The stimulation or “awakening” of this cryptic microbial secondary metabolism has naturally attracted the attention of synthetic microbiologists, who exploit recent advances in DNA sequencing and synthesis to achieve unprecedented control over metabolic pathways. One of the indispensable tools in the synthetic biology toolbox is metabolomics, the global quantification of small biomolecules. This review illustrates the pivotal role of metabolomics for the synthetic microbiology of secondary metabolism, including its crucial role in novel compound discovery in microbes, the examination of side products of engineered metabolic pathways, as well as the identification of major bottlenecks for the overproduction of compounds of interest, especially in combination with metabolic modeling. We conclude by highlighting remaining challenges and recent technological advances that will drive metabolomics towards fulfilling its potential as a cornerstone technology of synthetic microbiology

Combining evolutionary algorithms with reaction rules towards focused molecular design

Designing novel small molecules with desirable properties and feasible synthesis continues to pose a significant challenge in drug discovery, particularly in the realm of natural products. Reaction-based gradient-free methods are promising approaches for designing new molecules as they ensure synthetic feasibility and provide potential synthesis paths. However, it is important to note that the novelty and diversity of the generated molecules highly depend on the availability of comprehensive reaction templates. To address this challenge, we introduce ReactEA, a new open-source evolutionary framework for computer-aided drug discovery that solely utilizes biochemical reaction rules. ReactEA optimizes molecular properties using a comprehensive set of 22,949 reaction rules, ensuring chemical validity and synthetic feasibility. ReactEA is versatile, as it can virtually optimize any objective function and track potential synthetic routes during the optimization process. To demonstrate its effectiveness, we apply ReactEA to various case studies, including the design of novel drug-like molecules and the optimization of pre-existing ligands. The results show that ReactEA consistently generates novel molecules with improved properties and reasonable synthetic routes, even for complex tasks such as improving binding affinity against the PARP1 enzyme when compared to existing inhibitors.Centre of Biological Engineering (CEB, University of Minho) for financial and equipment support. Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UIDB/04469/2020 unit and through a Ph.D. scholarship awarded to João Correia (SFRH/BD/144314/2019). European Commission through the project SHIKIFACTORY100 - Modular cell factories for the production of 100 compounds from the shikimate pathway (Reference 814408).info:eu-repo/semantics/publishedVersio

The coevolution of industries and national institutions: Theory and evidence

A survey across space and time reveals that leading firms operating in global industries often cluster in one or a few countries. The paper argues that nations differ in how successful they are in a particular industry because coevolutionary processes linking a particular industry and national institutions powerfully shape the path of an industry.s development. Across a wide range of contexts, scientific progress and industrial leadership reinforce each other in spirals of cumulative national advantage. A historical case study of synthetic dyes from 1857 to 1914 provides a dramatic example of how these positive feedback processes gave German organic chemistry and German dye firms a dominant position in the world. Over time, the relative strength of a nation in a particular industry and the capability of the country in a relevant scientific or engineering discipline display a strong positive correlation. Additional shorter case studies of agriculture, packaged software, and biotechnology support this induced hypothesis. We argue that the exchange of personnel between industry and academic institutions, the formation of commercial ties between them, lobbying on each other.s behalf and direct support from state agencies constitute causal mechanisms that can explain why successful firms often cluster in particular countries. -- Die führenden Unternehmen eines Industriezweiges konzentrieren sich, obwohl sie auf einem internationalen oder globalen Markt agieren, oft nur in einer eng begrenzten Anzahl von Ländern . oder in nur einem Land. Auf der Grundlage verschiedener Fallstudien werden in diesem Artikel spezifische Verknüpfungen von Industrie und national geprägter Wissenschaftslandschaft aufgezeigt, die in einem Prozess enger gegenseitiger Einflussnahme zu einer jeweils herausragenden . dominanten . wirtschaftlichen Position führten. Die Untersuchung der internationalen Dominanz Deutschlands auf dem Gebiet der Herstellung synthetischer Farbstoffe vor dem Ersten Weltkrieg zeigt eine starke positive Wechselwirkung zwischen der Forschung auf dem Gebiet der organischen Chemie und der Marktstellung der farbstoffproduzierenden Unternehmen. Der Aufstieg bedeutender Unternehmen wie Bayer, BASF und Hoechst steht dabei über personellen Austausch, kommerzielle Beziehungen und gemeinsames Lobbying in so enger Verbindung zu den relevanten akademischen Institutionen und ihrer Entwicklung, daß von einem koevolutionären Prozess gesprochen werden kann. Eine derartige positive Korrelation und ein daraus entstehender spezifischer Vorteil wird durch die Betrachtung des Marktes für Computer-Software oder des derzeit vieldiskutierten Bereichs der Biotechnologie untermauert.Industry evolution,national institution,science-industry interface

Grounding knowledge and normative valuation in agent-based action and scientific commitment

Philosophical investigation in synthetic biology has focused on the knowledge-seeking questions pursued, the kind of engineering techniques used, and on the ethical impact of the products produced. However, little work has been done to investigate the processes by which these epistemological, metaphysical, and ethical forms of inquiry arise in the course of synthetic biology research. An attempt at this work relying on a particular area of synthetic biology will be the aim of this chapter. I focus on the reengineering of metabolic pathways through the manipulation and construction of small DNA-based devices and systems synthetic biology. Rather than focusing on the engineered products or ethical principles that result, I will investigate the processes by which these arise. As such, the attention will be directed to the activities of practitioners, their manipulation of tools, and the use they make of techniques to construct new metabolic devices. Using a science-in-practice approach, I investigate problems at the intersection of science, philosophy of science, and sociology of science. I consider how practitioners within this area of synthetic biology reconfigure biological understanding and ethical categories through active modelling and manipulation of known functional parts, biological pathways for use in the design of microbial machines to solve problems in medicine, technology, and the environment. We might describe this kind of problem-solving as relying on what Helen Longino referred to as “social cognition” or the type of scientific work done within what Hasok Chang calls “systems of practice”. My aim in this chapter will be to investigate the relationship that holds between systems of practice within metabolic engineering research and social cognition. I will attempt to show how knowledge and normative valuation are generated from this particular network of practitioners. In doing so, I suggest that the social nature of scientific inquiry is ineliminable to both knowledge acquisition and ethical evaluations