Expanding our enzyme search platform [CASE STUDY]

CASE STUDY

Expanding our enzyme search platform

BIOMATCHMAKER® (BMM), our proprietary enzyme search software, was first designed as a minimal viable product (MVP) to explore the enzymatic landscape of several alcohol dehydrogenases (ADH), with the aim to identify novel ADHs enzymes able to convert industrially relevant alcohol to corresponding ketones/aldehydes.

However, other relevant industrial processes requiring more complex and sophisticated enzymatic mechanisms remained elusive to our algorithm.

Would we be able to conduct an optimization of the BMM algorithm for it to work with any enzyme family, regardless of the complexity of their reaction? Moreover, would we be able to apply the BMM optimized version to discover new enzymes and expand the company’s pipeline?

To delimit the problem, we focused our efforts into…

Fill out the form below to download the full document:


    Press Release IDEA-PS project presentation

    ZYMVOL and CYGYC BIOCON join forces to develop a new computational platform capable of identifying sustainable enzyme inhibitors for detergent formulations


    CYGYC BIOCON and ZYMVOL start collaboration to improve sustainability of detergent formulation

    COMPANY NEWS

    CYGYC BIOCON and ZYMVOL start collaboration to improve sustainability of detergent formulation

    At ZYMVOL we’ve joined forces with biochemical company CYGYC BIOCON, through its BIOKATAL brand, to develop a new generation of sustainable detergents. The project, which has received funding from ACCIÓ’s Tecniospring INDUSTRY programme, aims to improve the performance of enzymes in detergent formulations to facilitate a transition towards more eco-friendly household solutions.

    Most detergent formulations contain enzymes, which are catalytic proteins used to eliminate different types of stains. For the formulation to work properly, enzymes must be deactivated or in a very low activity state, and only activated once they come into contact with water.

    This is especially important when it comes to proteases, an enzyme type that tends to degrade all other enzymes in detergent formulas. To maintain them in the mentioned low activity state when the detergent is not being used or under storage conditions, they need to be deactivated with what are known as «inhibitors».

    Currently, the majority of protease inhibitors used in detergents are compounds based in boron.

    Despite these inhibitors complying with strict European laws, they can still have a negative impact on the environment due to its toxicity towards some types of plants and insects. That’s why CYGYC BIOCON is committed to further improving the sustainability of its product line by eliminating the need for boron-based inhibitors.

     

    «With this project we continue working to offer ecological and sustainable washing solutions. This brings us a little closer to the milestone of obtaining environmentally neutral impact detergents»
    Dr. Sergi Abad, Biotechnology Technical Manager at CYGYC BIOCON

     

    By combining CYGYC BIOCON’s extensive experience in detergent formulations and ZYMVOL’s enzyme engineering know-how, both companies expect their innovation to lead to a much less contaminating solution that affects every household.

    Sustainable Detergents powered by Technology

    Under the name IDEA-PS: Inhibition of Detergent Enzymes Advanced Prediction Software, the project will consist in the development of a new computational platform – named ZYMEVOLVER-iDET – capable of identifying new, sustainable enzyme inhibitors for detergent formulations.

    Dr. Brian Jimenez-Garcia, Senior Researcher at ZYMVOL, will be the primary investigator leading this project.

     

    «By applying ZYMVOL’s technology, we expect to find inhibitors that can substitute the boron-based ones with greener alternatives. We hope that with this software, we will be able to help scientists make more effective formulations that will save resources, energy and water»
    Dr. Brian Jimenez-Garcia, Senior Researcher at ZYMVOL

     

    With the support of Tecniospring INDUSTRY, a programme powered by the Catalan Agency for Business Competitiveness (ACCIÓ), the IDEA-PS project has an established duration of 2 years and expects to achieve the first results by the end of 2022.

    Thanks to this innovation, both CYGYC BIOCON and ZYMVOL calculate they can achieve a significant decrease in the environmental footprint of current detergents.


    Obtaining Improved Enzyme Variants without Structural Data [CASE STUDY]

    CASE STUDY

    How we obtained improved variants of an enzyme (through in silico modeling) without structural data

    In August 2020 we started a collaboration with a customer from the Biotech sector who wanted to increase the activity and specificity of an enzyme for a target substrate.

    However, we were facing an outstanding situation. Our customer’s project enzyme had:

    • No known crystal structure
    • Very few known sequences similar to the wild-type, hindering the use of sequence-based tools
    • Unavailability of appropriate templates to build a good quality homology model

    When we met with our customer, they had already performed…

    Fill out the form below to download the full document:


      A look at our Enzyme Technology: Molecular Modeling

      This post has been written by ZYMVOL's Senior Researchers Marina Cañellas and Lur Alonso.

       

      Zymvol’s core technology is Molecular Modeling, which – along with bioinformatics – allows us to understand the mechanistic details under enzymatic function and use the generated knowledge to search and tailor biocatalysts towards improved properties.

      In this way, by integrating molecular modeling-based strategies at distinct levels of theory, we can identify the best target enzymes and perform their custom design in less than one month!

      So, what is Molecular Modeling?

      Molecular Modeling refers to a collection of in silico methods that model or mimic the behavior of molecules, ions and/or particles (Nature Subjects). Their main goal is to provide knowledge on the chemistry, structure, dynamics and function of these systems. 

      By definition, In silico refers to “conducted or produced by means of computer modelling or computer simulation” (Oxford Dictionary). Simply put, as these methods require huge amounts of calculations, they are performed by computers.

      Molecular Modeling has a wide range of applications in many different areas:  computational chemistry, computational biology, drug design, material science… and for this reason it has become a rapidly growing field during the last decades. 

      The large variety of systems that can be modeled range from small chemical systems (like the reaction mechanism between two substrates) to larger biological molecules (such as enzymes, antibodies or DNA) and material/molecular assemblies (like supramolecular polymers (Bochiccio, 2017; Frederix, 2018), protein-based assemblies (Soni, 2017), and molecular machines (Aprahamian, 2020).

      Although many limitations still exist, they have shed light on some features like functions, processes, and catalytic pathways.

      QM and MM

      Because of the high complexity underneath molecular systems, such as enzyme-catalyzed reactions, there is not a single in silico technique that suffices for their full modeling. In this way, two main categories of computational methods have been developed at different levels of description: 

      • Those describing systems from an electronic point of view (Quantum Mechanics (QM) methods, this is the deepest level of accuracy to study a system!)
      • Those that describe systems at the atomic level (Molecular Mechanics (MM) methods).

      QM methods provide an accurate representation of the system, enabling the description of reaction mechanisms at the electron level, but are computationally very expensive.

      On the other hand, MM methods allow the study of larger molecules like proteins, enabling sampling the overall system flexibility, but cannot represent bond-breaking/bond-forming events. As a solution to this issue, the benefits of both strategies can synergize into hybrid schemes, such as combined Quantum Mechanics/Molecular Mechanics methods (QM/MM), enabling the accurate description of large biological phenomena and reactions. QM/MM was awarded with the Nobel Prize in 2013 to scientists Karplus, Levitt, and Warshel.

      Adapted from Dr. Marina Cañellas PhD thesis “In silico molecular modelling and design
      of heme-containing peroxidases for industrial applications” 2018.

       

      The benefits of Molecular Modeling

      Why do we think that relying only on bioinformatics is not enough?

      Of course, there are some perks to it.

      • Allows to simulate an entire chemical system in the computer
      • It has unique potential to offer detailed atomic-level insights into the studied systems 
      • Allows to predict new mutant variants beyond currently available data.
      • Allows to perform millions of screening/mutations in one day, saving up to 90% of time (compared to experimental procedure). 
      • Saves resources since only a low number of enzymes are tested in the lab (maximum of 300 enzymes tested in the lab with Zymvol’s technology instead of up to millions using exclusively experimental approaches)

      As pointed out before, Molecular Modeling techniques are always complemented with sequence-based strategies; the increasing field of bioinformatics complements the predictions and adds new hints hidden on the protein sequence! 

      Bioinformatics evaluates the vast amount of data collected daily worldwide and extracts extremely valuable information by applying the proper tools and algorithms. 

      Molecular modeling complements wet lab experiments. The way of maximizing success and development in our services Enzyme Search and In silico design is through the close collaboration between dry and wet lab. Considering these two areas as iterative approaches allows scientists to gather a deeper and faster understanding of, in this case, biocatalysis. While computational predictions need to be validated by experimental techniques, wet lab experiments can also benefit from computational approaches by reducing the research time and costs and giving valuable atomic-level insights. In this way, by analyzing huge datasets (sequences, mutant libraries, enzymatic properties, …), lab work is significantly reduced. This enables scientists to obtain results in shorter times and accelerates research/industrial projects, which is of imperious importance for the Industrial Sector (Truppo 2017).

      Molecular Modeling in use

      Due to the exponential increase that computational resources and strategies have undergone in the last decade, in silico simulations have gained a spot guiding the experimental work in a wide range of areas. (Check the following references for more information on these topics: Hollingsworth & Dror, 2018, Schwaigerlehner et al., 2018, Blog article Ebejer and Baron 2020, as well as more trend research like the one related to COVID19 (Talk by Strauch, 2021)). 

      Some fields that are benefited by these in silico methodologies include:

      • Drug discovery (disease mechanisms)
      • Neuroscience (for example, protein-protein interactions)
      • Advanced therapies (for example, antibody engineering)
      • Biocatalysis (for example, directed evolution)

      Some practical examples:

      • Elucidate enzymatic mechanisms, understanding enzymes’ catalytic power and enzyme design.
      • Simulation of binding-free energies of small molecules (e.g drugs to their targets).
      • Search for wild type enzymes to perform a particular non-natural reaction.

      Getting the best out of Molecular Modeling

      As it has been stated, Molecular Modeling is one of the most important approaches we use to provide our Enzyme Search and In Silico Design services. Thanks to our innovative approach, at ZYMVOL we are able to take into account the following features:

      • Solvent effects (by incorporating explicit waters in our simulations) 
      • Quantic effects 
      • Dynamic changes of the protein backbone (backbone flexibility)
      • Distant mutations
      • Side chain flexibility

       

       

      Normally, it's hard to find companies who work with all these features, since techniques are very expensive, time consuming or require high specialization. 

      The truth is that in this area, the customer moves in the trade off triangle of price-time-expertise: either techniques are very expensive (and/or time-consuming) or require scientists with outstanding degree of specialization to successfully carry out projects. 

      What you usually find in the market is:

      • Companies relying only in bioinformatics and experimental work (↑time, ↑price, ↓specific expertise)
      • Companies offering only experimental approach (↑time, ↑price, ↓specific expertise)
      • Companies that offer excellent software, but it is very difficult to achieve quick, reliable results without the assistance of an expert.  (↑time, ↓price, ↓specific expertise).

      However, taking all of these features into account is truly beneficial, as it means:

      • More realistic simulations
      • More accurate results and with the unique advantage 
      • The possibility of obtain results in significant short times

      Molecular Modeling is a truly powerful tool and it has contributed significantly to our enzyme discovery and design projects. Thanks to it, we can help many industries transition to the use of biocatalysts and make the industry greener.

      Do you still have questions related to molecular modeling? Drop us an email: info@zymvol.com

       


      References:

      Aprahamian, I. (March 3, 2020) The Future of Molecular Machines. ACS Cent. Sci., 6(3), 347-359

      Bochicchio, D.; Pavan, G.M. (February 11, 2018) Molecular modelling of supramolecular polymers. Advances in Physics:X, 3(1)

      Ebejer, J.P; Baron, B. (June 14, 2020) Dry- and wet-lab research: two sides of the same coin. Times of Malta. https://timesofmalta.com/articles/view/dry-and-wet-lab-research-two-sides-of-the-same-coin.798297

      Frederix, P.W.J.M.; Patmanidis, I.; Marrink, S.J. (April 24, 2018). Molecular simulations of self-assembling bio-inspired supramolecular systems and their connection to experiments. Chem. Soc. Rev., 47, 3470-3489

      Hollingsworth, S.A.; Dror, R.O. (Sept 19, 2018) Molecular dynamics simulation for all. Neuron, 99(6), 1129-1143

      Nature. Molecular Modelling. https://www.nature.com/subjects/molecular-modelling

      Soni, N.; Mashusudhan, M.S. (June, 2017) Computational modeling of protein assemblies. Current Opinion in Structural Biology, 44, 179-189

      Schwaigerlehner, L; Pechlaner, M; Mayrhofer, P; Oostenbrink, C; Kunert, R. (May 11, 2018) Lessons learned from merging wet lab experiments with molecular simulation to improve mAb humanization. Peds, 31(7-8), 257-265

      Truppo, M.D. (April 18, 2017) Biocatalysis in the Pharmaceutical Industry: The Need for Speed. ACS Med Chem Lett. 8(5): 476-480


      Why is Green Chemistry important? Origins and Industry Impact

      For the past few decades, the scientific community as well as society as a whole has raised its voice on the impact our actions have on the environment, pressing authorities and looking for solutions to address the problem. One of the main focuses has been set on Chemistry, as many “traditional” chemical processes are not sustainable in the long run, with devastating consequences for the environment and quality of life.

      In this context, there’s a term that has been slowly, but steadily, gaining traction: Green Chemistry

      As the International Union of Pure and Applied Chemistry (IUPAC) puts it, Green Chemistry (also known as Sustainable Chemistry) encompasses the “invention, design, and application of chemical products and processes to reduce or to eliminate the use and generation of hazardous substances”.

      But what does this all mean? Why is green chemistry important and how does it contribute to the world’s sustainable development?

      Let’s start by going back in history…

      The Origins of Green Chemistry

      According to the American Chemical Society (ACS), the term “Green Chemistry” was first coined by the US Environmental Protection Agency - Office of Pollution Prevention and Toxins around the 1990s.

      The idea of a greater consciousness regarding chemistry had been gaining power since the 60s and 70s, however, it was mostly focused on banning dangerous toxins like DDT and “cleaning up” the aftermath of certain chemical activities. It was not until the 80s and 90s that scientists started thinking differently about their way of doing chemistry, shifting the focus on how to prevent pollution before it even took place.

      Then, in 1998, two scientists named Paul Anastas and John C. Warner published what today is popularly known as the "Twelve Principles of Green Chemistry".

      The Twelve Principles of Green Chemistry

      First published in the book “Green Chemistry: Theory and Practice”, the Twelve Principles of Green Chemistry is a set of guidelines that other chemists can consult to work towards a more sustainable chemistry. The book marked a new era, by helping consolidate a movement that was destined to define how modern chemistry is made.

      The principles highlighted in Anastas and Warner’s book are:

      1. Waste Prevention
      2. Atom Economy
      3. Less Hazardous Chemical Syntheses
      4. Designing Safer Chemicals
      5. Safer Solvents and Auxiliaries
      6. Design for Energy Efficiency
      7. Use of Renewable Feedstocks
      8. Reduce Derivatives
      9. Catalysis
      10. Design for Degradation
      11. Real-time analysis for Pollution Prevention
      12. Safer Chemistry for Accident Prevention

      Green Chemistry in Industry

      Now that sustainability is on everybody’s top-of-mind, Green Chemistry is more important than ever. Just think about the amount of industries that rely on chemistry and whose activity has a great impact on the environment: pharma, agriculture, colorants, materials, consumer products... to name a few. 

      This in part is due to the clear increase in awareness about environmental pollution. Especially since the last decades, people are becoming aware that we, as humans, are stressing the planet’s finite resources, and acknowledging that our consumption and waste have to go somewhere. And the current COVID crisis has consolidated this feeling. Just to mention some facts, there is fair evidence about:

      If you watch the news, you might have noticed that some institutions are working non-stop to keep this issue present:

      And special laws and regulations are being developed to promote more environmentally friendly, sustainable production processes and industries: REACH normative in European Union, ISO 14001, to name some of them.

      In parallel, consumers are concerned about the impact the products they buy have in the environment and in their own bodies. Multiple initiatives inviting consumers to choose more “consciously” are nowadays on the front line, and they are demanding products that are respectful in the whole production chain: from manufacturing to recyclability. 

      Having said all this, perhaps you are not very sure yet about the difference between green chemistry and general chemistry. The best way to describe it is that Green Chemistry’s main goal is to achieve the same or equivalent chemical reactions with a decrease in environmental damage.

      And how is this accomplished?

      Some techniques that are used for this aim include:

      • Catalysis: as mentioned in our first blog post, catalysis is the process of increasing a chemical reaction’s rate by the addition of an element denominated catalyst (like enzymes!), that is not consumed during the reaction and therefore can act repeatedly.
      • Synthetic biology: by applying engineering principles, the goal is to redesign and create new biological systems with the aim of providing novel solutions. Examples of this could be the creation of lab-grown meat, synthetic insulin or biofuels produced by algae.
      • Chemical synthesis: as the Nature journal definition says, chemical synthesis is “the process by which one or more chemical reactions are performed with the aim of converting a reactant or starting material into a product or multiple products”.

      Why are industrial enzymes an example of Green Chemistry?

      Maybe you are still wondering how green chemistry can help decrease pollution.

      Like we mentioned earlier, Green Chemistry focuses on sustainability by looking for ways of preventing pollution, hazardous activity and resource waste. That’s why the use of industrial enzymes is such a sought-after solution for many companies who want to shift to greener production processes.

      As biocatalysts, enzymes have a set of properties more beneficial than their non-enzymatic counterparts:

      • They are highly selective and specific, which allows chemists to have more control over their desired results.
      • They are effective under mild temperatures, which means significant energy savings.
      • They do not generate toxic waste.

      As you can see, enzymes are pretty powerful! The main problem is adapting these enzymes to an industrial setting, which usually means tweaking the structure of an already existing enzyme to give it new features and make it work under certain conditions.That’s why at Zymvol we work to expand the use of green chemistry by creating custom-made enzymes for different industries. With some time and effort, we can make the world become a little bit greener.

       


      References:

      American Chemical Society. Green Chemistry History. https://www.acs.org/content/acs/en/greenchemistry/what-is-green-chemistry/history-of-green-chemistry.html 

      CompoundChem (September 24, 2015). The Twelve Principles of Green Chemistry: What it is & Why it Matters. https://www.compoundchem.com/2015/09/24/green-chemistry/

      Nature. Chemical Synthesis. https://www.nature.com/subjects/synthesis 

      European Environment Agency (March 25, 2021) Synthetic biology and the environment. https://www.eea.europa.eu/publications/synthetic-biology-and-the-environment 

      Aatresh, A.; Cumbers, J. (September 22, 2019) Can Synthetic Biology Make Insulin Faster, Better and Cheaper?. Synbiobeta. https://synbiobeta.com/can-synthetic-biology-make-insulin-faster-better-and-cheaper/ 

      Straathof, A.J.J.; Adlercreutz, P. (2000). Applied Biocatalysis (2nd Ed.). CRC Press.


      What are the Colors of Biotech?

      Modern biotechnology arose in the late 20th century and is currently proving to be one of the key solutions to today's problems, especially regarding health and the environment.

      According to the UN Convention on Biological Diversity, Biotechnology is defined as any technical application that uses biological systems, living organisms or parts of them to make or modify products or processes with specific uses.

      Giving that those products can be of many types, Biotechnology can cover a wide number of applications: from increasing the quality and resistance of farm crops, to keeping hospital patients healthy by keeping track of their vital signs -and, of course, engineering enzymes for industrial use.

      The Colors of Biotech

      As a way to structure this vast array of biotech possibilities, scientists started to categorize them by color. Each branch, a different color. That’s why you’ll often hear about the Rainbow Code of Biotechnology.

      So what does each color represent in this biotech rainbow?

      • Blue Biotech covers the aquatic and marine fields, by using ocean resources to create products and industrial applications.
      • Green Biotech has to do with everything agriculture-related, focused on improving crops in an accurate, targeted way.
      • Red Biotech centers on Healthcare, by developing an advanced class of drugs and therapies
      • Yellow Biotech covers Food Production
      • Brown Biotech for when Deserts and dry regions are involved
      • Golden Biotech is focused on the use of Bioinformatics, Computational Science, Agile organization and analysis of biological data. We recently wrote a post about what is Golden Biotech in more detail.
      • Gray Biotech encompasses the Environment and biodiversity, environmental protection, maintenance of biodiversity and removal of pollutants
      • White Biotech is for Industrial processes and gene based technologies, as well as the use of enzymes and microorganisms to produce biobased products
      • Purple Biotech is reserved for the laws, ethics and philosophy revolving around biotechnology
      • Black Biotech, as you can imagine, focuses on a darker topic: Bioterrorism and biological warfare

       

      At ZYMVOL we are part of the golden branch of biotechnology, since we use computational approaches to improve and enable the discovery of industrial enzymes. For that, we use technology based on computational molecular modeling, machine learning and other tools that allow us to fully understand and work with the chemical structure and interactions between enzyme, substrate and its environment.

      We are golden, but our technology can help develop solutions in all other colors!

      Discover how we help our customers in Pharma, Chemicals, Biotech and other industries here.

       


      References:

      Convention on Biological Diversity (2006). Convention Text. Article 2. Use of Terms. https://www.cbd.int/convention/articles/?a=cbd-02

      Kafarski, P. (2012). Rainbow Code of Biotechnology. CHEMIK. 66(8), 811-816.


      Golden biotech: what it is and why it matters

      You might be wondering: “what is golden biotech?”. The answer is rather simple: a biotechnology field that uses computer science as a main driving force. But do you know why it’s often referred to as “golden”? Or what exactly does it entail when taken into practice?

      The color code of biotech

      First of all, Golden biotech is known as “golden” because of the Rainbow Code of Biotechnology: a way to divide biotechnology’s vast array of applications into different categories, each one defined by a color.

      Through this code, we know that when someone is talking about red biotech, they’re referring to health and medical applications; and when they’re talking about white biotech, they’re mostly talking about industrial uses.

      All colors of the Biotech Rainbow are important, but what sets Golden Biotech apart is that it revolves around computers. For a technology to be considered golden, it has to rely heavily on some form of computational technique.

      Golden biotech is a fairly recent addition to the biotech spectrum, but due to increasing advances in computer technology, one with a lot of potential to keep on growing in the following years.

      Some of the main areas included in golden biotech are:

      • Bioinformatics. Field that focuses on analyzing large sets of biological data.
      • Nanotechnology. Field that uses technology at a nanoscale, or in other words, in atomic, molecular and macromolecular levels.
      • Computational Biology. Although closely linked to Bioinformatics, Computational Biology consists of using computational methods to develop models for the study of biological systems. This means relying on technologies like Machine Learning, Algorithms, Big Data (to name a few) for building these models.

      Zymvol: an example of Golden Biotech company

      Now that you know the definition of golden biotech and the main technologies behind it, you might say: “ok, but what does it really look like taken into practice?”

      Just take a look at us. At ZYMVOL, we are golden. And is not that we are pretentious: it’s because we work in the golden branch of biotechnology.

      At our company, we use a computational approach to improve and enable the discovery of industrial enzymes. We perform what we call “in silico enzyme evolution”, that is, engineer enzymes in the computer through molecular modeling, machine learning and other computer driven technologies. This allows us to fully understand the chemical structure and interactions between the enzyme, the substrate and their environment.

      Take a look at the following video. What we do at ZYMVOL in a nutshell:

       

       

      Through computer simulations we reproduce the enzyme, its environment and the desired reaction (substrates that interact with the enzyme) to be carried out: we perform different strategic mutations (amino acid substitutions) along the enzyme’s sequence and test its performance, looking at variables such as stability, activity or selectivity.

      Thanks to computer simulations, we came up with the best combinations to test in the lab. We provide to our customers the sequences of the top performing candidates, so they produce in the lab only what matters.

      This, at large, is the heart of golden biotechnology!

       


      References:

      Brown, K. (2018) Gold Biotechnology. Wikitech. https://wikitech21.wordpress.com/2018/08/26/gold-biotechnology/

      DaSilva, Edgar J. (2004). The Colours of Biotechnology: Science, Development and Humankind. Electronic Journal of Biotechnology, 7(3), 01-02.