The flow of information from protein sequence over structure to physiological function has been boggling physicists’, chemists’, and biologists’ minds for over half a century. First postulated by Christian Anfinsen in the 1970s, the ‘thermodynamic hypothesis’ describes a unique relationship in which the amino acid sequence of a protein should be sufficient to determine its structure [1]. Yet, it was during the same time when Cyrus Levinthal famously noted that, theoretically, it would take longer than the age of the universe for a typical protein to sample all possible conformations in order to reach its correct fold [2]. Opening one of the biggest challenges in biology, advances in computational methods, as well as the drastic increase in experimental structures and sequences being published, just recently narrowed down the ‘sequence-structure gap’ that Anfinsen and Levinthal opened. Culminating in AlphaFold 2 [3], sequence-based structure prediction has reached astonishing accuracy, representing a huge leap forward in biology and also in drug discovery.
 
Is it that simple? While it is true that structure models represent a great starting point for many research endeavors, the same scientific advances that brought us AlphaFold revealed gaps in the sequence-structure-function paradigm. It is now common knowledge that proteins are not static at all, as suggested by models obtained from predictions or crystallographic structures, but highly dynamic. These dynamics range from bond vibrations to large conformational changes, come in networks, and often modulate protein function – a phenomenon collectively described as allostery [4]. But what is the relationship between sequence and the structural dynamics that govern function? If the sequence-structure-function paradigm holds true, these dynamics should be imprinted in the sequence and should evolve alongside the often highly conserved active site of a protein. More specifically, to maintain biological robustness, a network of energetically coupled residues should translate into a joint evolutionary constraint between each participating residue - they co-evolve or co-mutate [5].
 
Besides positional conservation, information about co-evolution is contained in multiple sequence alignments (MSAs) of homologous sequences, as these reflect the ‘evolutionary history’ of a protein family. By applying statistical models to MSAs, the interdependency of the variability of each sequence position, the ‘co-evolutionary coupling’, can be obtained and can be interpreted as direct or indirect physical connectivity between residues. A plethora of methods that build on this principle have been developed and succeeded in deciphering residue-residue couplings for structure prediction and identification of functional domains for ligand binding or allosteric regulation [6]. However, experimental validation of dynamic co-evolving networks that modulate protein function is challenging. In particular, when these dynamics take place in the absence of global structural changes.
 
In a recent study, Torgeson et al. [7] combined co-evolutionary analysis and nuclear magnetic resonance (NMR) spectroscopy to identify previously undescribed dynamic networks of the protein tyrosine phosphatase (PTP) PTP1B. PTP1B’s structure, dynamics and function, as well as that of its homologs have been rigorously characterized, making it an ideal system to study the impact of co-evolution on functional dynamics.
 
Torgeson et al. applied so called pseudolikelihood maximization direct coupling analysis (plmDCA) [8] to an MSA of PTP1B homologs to derive co-evolutionary couplings and then used a spectral clustering approach to split the structure into strongly coupled co-evolving domains, referred to as evolutionary domains (EDs) [9]. Supporting the idea of co-evolutionary analysis to identify functionally critical residue groups, four of the obtained EDs have been previously verified experimentally in PTP1B. However, further clustering revealed additional, yet uncharacterized subdomains.
 
More than 16 Å from away from the active side, one of these subdomains contains an extended hydrophobic pocket that appeared to be, other than the already characterized EDs, contiguous in space rather than in sequence. Selectively mutating central positions in the domain, either independently or as triple mutants, reduced thermal stability in all cases, but increased the catalytic turnover rate (kcat) of the enzyme by more than 2-fold. Strikingly, structural analysis by 2D-[1H,15N] and 2D-[1H,13C] transverse relaxation optimized spectroscopy (TROSY) NMR and X-ray crystallography revealed no large conformational changes due to the mutations and previously described allosteric pathways of PTP1B remained unchanged.
 
In the absence of global structural change, Torgesen et al. reasoned that an increase in kcat could be driven by side-chain dynamics in the µs – ms time range – a relationship that has been previously shown to govern the catalytic cycle of PTP1B [10]. To proof this hypothesis, they conducted so called constant time 13C Carr-Purcell Meiboom-Gill (ct-CPMG) relaxation dispersion experiments that allow for measurements of side-chain dynamics and extraction of a model that describes the conformational exchange between two populations A and B with the exchange rate kex. In measuring relaxation dispersion in the absence and the presence of a substrate-mimicking inhibitor, they could show that under conditions of catalysis (i.e., when the inhibitor is bound) the overall fast dynamics of the free mutated PTP1B are quenched and that residues cluster into three groups based on their kex values. Although these three groups were also identified for the wildtype, the exchange rates of the groups differed. Remarkably, one group contained many residues of the distal co-evolutionary subdomain described above and showed ~2-fold increase in kex from wildtype to mutant PTP1B – an increase that mirrors the 2-fold increase in kcat that was observed in enzymatic assays. The correlation of catalysis and side-chain dynamics in this group of residues was further supported by the resemblance between kcat and the fitted unidirectional exchange rate kAB. Most importantly, this also reflects the reciprocity of this regulatory pathway, because changes in the active site, e.g., binding of a substrate, changed the dynamics in the subdomain, while perturbations in the subdomain due to mutations influenced catalytic activity.
 
But what is the purpose of this regulatory subdomain? While highly conserved residues of the hydrophobic subdomain support the N-terminal portion of an α-helix, which directly connects to the catalytic loop, less conserved residues flank the C-terminal portion of that α-helix. Accordingly, sequence variations in this less conserved part could enable fine-tuning of the kinetic properties of PTPs without perturbing specificity of the active site or the allosteric regulation.
 
In mechanistically proving the relationship between a co-evolving non-catalytic subdomain and its impact on enzymatic catalysis Torgesen et al.’s study provides a good view on how functional dynamics can leave a footprint in protein sequences throughout evolution. The combination of co-evolutionary analysis with NMR-based analysis of side-chain dynamics proved to be critical in dissecting the regulatory network, otherwise invisible in static X-ray structures. Although this is just one of the few examples in which the energetic connectivity that underlies residue co-evolution was studied experimentally in detail, the study demonstrates that sequence analysis can be instrumental in mechanistic studies of protein dynamics. Finally, and most importantly, by showing that functional dynamics are indeed encoded in sequence, the study supports addition of dynamics as a missing part to the sequence-structure-function paradigm.

References
1. Anfinsen, C. B. Principles that Govern the Folding of Protein Chains. Science 181, 223–230 (1973).
2. Levinthal, C. Are there pathways for protein folding? J Chim Phys 65, 44–45 (1968).
3. Jumper, J. et al. Highly accurate protein structure prediction with AlphaFold. Nature 596, 583–589 (2021).
4. Wodak, S. J. et al. Allostery in Its Many Disguises: From Theory to Applications. Structure 27, 566–578 (2019).
5. Göbel, U., Sander, C., Schneider, R. & Valencia, A. Correlated mutations and residue contacts in proteins. Proteins Struct Funct Bioinform 18, 309–317 (1994).
6. Juan, D. de, Pazos, F. & Valencia, A. Emerging methods in protein co-evolution. Nat Rev Genet 14, 249–261 (2013).
7. Torgeson, K. R. et al. Conserved conformational dynamics determine enzyme activity. Sci Adv 8, eabo5546 (2022).
8. Ekeberg, M., Lövkvist, C., Lan, Y., Weigt, M. & Aurell, E. Improved contact prediction in proteins: Using pseudolikelihoods to infer Potts models. Phys Rev E 87, 012707 (2013).
9. Granata, D., Ponzoni, L., Micheletti, C. & Carnevale, V. Patterns of coevolving amino acids unveil structural and dynamical domains. Proc National Acad Sci 114, E10612–E10621 (2017).
10. Torgeson, K. R., Clarkson, M. W., Kumar, G. S., Page, R. & Peti, W. Cooperative dynamics across distinct structural elements regulate PTP1B activity. J Biol Chem 295, 13829–13837 (2020).
 

Saturday, 6 am. Berlin’s central station is deserted (apart from a few Oktoberfest aficionados on their way to Munich) when I board the train that would take me to Budapest. One year into my PhD, time has come to depart for my first secondment. After having moved to Berlin, struggled to find an apartment and settled in a new lab, the script repeats itself. Luckily, one gets more and more used to relocations over time. Packing and saying farewells become a routine and – let’s be honest – the 2.5 months that I will spend in Budapest are a foreseeable period of time. Based on my first impressions, Budapest is a bustling city, enchanting with its mixture of crumbling Art Nouveau buildings, modern skyscrapers and panel buildings (Panelház) that reflect its moved history. It seems to be a wonderful place to live, and probably most important for me right now, to do science! I was provided a very warm welcome by my host lab, the Medicinal Chemistry Research Group at the Research Center for Natural Sciences and am now looking forward to getting my chemistry running here.
 
When I was younger, I assumed that one would need to become a world-renowned music star or at least a diplomate to travel the world for work and live in different countries. Since I cannot sing and my French is rudimentary, I ruled out these career options early on. The thought that a career in science would get me there had never occurred to me. University studies, conferences, secondments – the list of occasions for travel and stays abroad as a scientist (as a chemist in my case) is long. The basic principles of chemistry and physics apply across borders; the stereoselectivity of an SN2 reaction is the same in Canada and Cameroon, and dichloromethane will form the lower layer in a liquid-liquid extraction with water anywhere around the globe. The language of chemical formulas and mathematical expressions is beautifully universal. Consequently, work in science is predestined for international exchange. I like to think of science as a connective link between people and cultures but of course, it is a valid question why this cross-country mobility is important and how society in general benefits from it.

Taking a broader view on the meaningfulness of cross-border scientific exchange, I am convinced that it does not only accelerate scientific progress but likewise enhances multilateral collaboration to tackle the most pressing challenges of our time. It makes us aware that people anywhere around the globe are asking the same scientific questions and work hard to answer them. Collaboration in science can open hearts and doors to initiate partnerships in entirely different fields. The experience abroad gives us the possibility and at the same time responsibility to advocate for intercultural communication and tolerance towards different viewpoints, promoting diversity in our communities.
On a personal level, I realize that each stay abroad confronts me with different opinions and ways of living, making me more approachable and understanding. I have become more resilient and self-confident by overcoming unanticipated challenges. Over time, I have learned most problems can actually be solved, often with the help of others. Moving to different countries has sensitized me for things that are not going well in places where I have lived before and, on the other hand, made me appreciate even more those things that were working out smoothly. Of course, personal development is one thing, but I am also convinced that each stay abroad makes me improve on a scientific level. During the current secondment in Budapest, for instance, I am re-learning lab-techniques that I am rarely using in Berlin (simply because I was not aware of their applicability to certain problems) but that might save me a lot of time during my daily work. I am also learning how to perform experiments, types of chemical reactions and work procedures that are entirely new to me but standard in my Hungarian host lab. Taking this knowledge back to Berlin and sharing it with my colleagues there, will benefit all of us. Finally, working and discussing with my new colleagues, who have different backgrounds and experiences, makes me see certain things, e.g. steps of a procedure, from a different perspective. This deepens my understanding of the respective processes and makes me question routine operations. Of course, I am very much hoping that this process of knowledge sharing is not one-way but mutual to make this experience most rewarding for everyone involved.

Researcher’s Night is a vibrant festival of research, technology and innovation that takes place every year on the last Friday of September in many cities across the European continent. In Athens, it is hosted by one of the oldest and most prominent university foundations of the country, the National and Technical University of Athens, and it attracts numerous professionals from the educational field -teachers, professors, officials from the Ministry of Education- and, mostly, school and university students: children, teenagers and young adults aged 4 to 25.

Given its non-specialized audience that mainly consists of younger individuals, the central concept of this particular event is for researchers to share their work in a more creative and original manner in order to give visitors the opportunity to gain a more hands-on perspective of their scientific activities.

ALLODD successfully participated in this year's Research's Night in Athens, giving the opportunity to more than 250 interested individuals of all ages to get to know ALLODD Network, its objectives and actions. Being the first ITN to explore the concept of allostery in drug discovery, ALLODD aims to train the next generation of young scientists to exploit this concept and set the foundation for the emergence of the field. Cournia Lab was there in Researcher's Night in Athens, to communicate the science behind ALLODD to the general public. Such actions are of great importance and a major goal of the network, in order for more people to get familiar with the role of allostery in drug discovery.

You can find the material of the event by clicking in the button below.

GPCRs are a large family of transmembrane proteins representing a renowned target in drug discovery. Classical GPCR drugs are simply developed by targeting their orthosteric binding sites, yielding compounds that either activate or inactivate the protein. The main problem with this approach is that these sites are highly conserved among GPCR subfamilies, and this causes poor selectivity and possible side effects.
 
For this reason, in recent times the development of allosteric drugs, targeting GPCRs at sites that are different from the orthosteric binding sites, is getting increasingly relevant. The existence of such drugs has opened up the way for new therapeutic approaches and enriched the possible ways to modulate the functions of GPCRs1.
 
Many studies have underlined the importance of allosterism in the context of GPCR dimerization or higher-order oligomerization in the control of the physiological responses they modulate. Indeed, for many years, GPCRs have been studied as single functional units (i.e., monomers)1. However, recent evidence suggests that GPCRs can also work as higher-order oligomers constituted by equal (homo) or different (hetero) monomers.

In the case of oligomers, allosterism has a dual nature. On the one hand, a ligand alters the conformation of one monomer which then binds and modulates the configuration of the interacting receptor. On the other, the monomer itself can be considered as the allosteric modulator altering the conformation of the associated receptor, modulating its downstream efficacy and ligand affinity.
 
Therefore, GPCR oligomers have the potential to markedly expand the diversity and specificity of G protein-coupled receptor signaling, particularly in neural cells, where a few key receptors have been implicated in many neurological and psychiatric disorders, including addiction.
                       
Several approaches have been designed to develop new drugs specifically targeting GPCR dimers. One possible way is to design a so-called bivalent ligand 2, a molecule composed of two pharmacophores that span the length of the dimer allowing it to dock at both ligand binding sites simultaneously. An example of this was reported by Gmeiner et al. in 20163 with a study focused on targeting the D2R- NTS1R heteromer via three different bivalent ligands. In addition to this, it is also possible to develop bitopic ligands that bind the allosteric site of a monomer and simultaneously modulate the functions of the other associated functional unit. This is the case for instance of the SB269652 allosteric modulator of the Dopamine D2 dimer4.
 
 
 
 

1. D. Wootten, A. Christopoulos, P. M. Sexton, Emerging paradigms in GPCR allostery: implications for drug discovery, Nat Rev Drug Discov 12(8):630-44. (2013)
2. C. Hiller, J. Kühhorn,  P. Gmeiner, Class A G-Protein-Coupled Receptor (GPCR) Dimers and Bivalent Ligands, J. Med. Chem. 56 (17):6542–6559.  (2016)
3. H. Hübner, T. Schellhorn, M. Gienger, C. Schaab, J. Kaindl, L. Leeb, T. Clark, D. Möller,  P. Gmeiner, Structure-guided development of heterodimer-selective GPCR ligands, Nat. Commun. 7, 12298 (2016)
4. J. R. Lane, P. Donthamsetti, J. Shonberg, C. J. Draper-Joyce, S. Dentry, M. Michino, L. Shi, L. López, P. J. Scammells, B. Capuano, P. M. Sexton, J. A. Javitch, A. Christopoulos, A new mechanism of allostery in a G protein-coupled receptor dimer, Nat. Chem. Biol. 10:745–752 (2014)
   

I began my PhD project at the Charité Institute shortly after moving to Berlin in the end of April of this year. Unfortunately, I had what I would qualify as a bit of a rough start. I had moved to another country before a few years ago already and thus thought I had an understanding of what to expect, but I underestimated how much of a challenge not being fluent in the language was going to be, especially with regard to finding a place to live. Additionally, I had to learn to perform long and complicated experiments unlike anything I had done previously. This, combined with a host of administrative issues, meant that the first few months of my PhD project were more difficult than anticipated.

And although luckily these issues did end up slowly but surely resolving themselves, the ALLODD workshop in Barcelona was still fortuitously timed. The change of pace, the interesting lectures and especially the opportunity to finally meeting my fellow ESRs from the program in person for the first time (as well as a number of the PIs) as I was unfortunately unable to attend the first workshop meeting in Vienna physically. The setup also facilitated networking, which I can otherwise find a bit daunting.

I was especially reminded of how interesting the field of GPCRs can be, both in academia and in the industry, and this comforted me in my decision to do a PhD centering on the study of the GPCR MC3R was indeed the right choice for me.

Furthermore, MC3R in particular seems to be on the rise in terms of the interest accorded to it by the scientific community. Indeed, it has been considered in the past to have a redundant role to its relative MC4R due to both having loss of function mutations connected to obesity. However, as it turns out the phenotype of these mutations for MC3R, unlike MC4R, includes an increase of the fat mass compared to lean mass as well as the mice models having trouble putting weight back after a period of restricted feeding. Moreover, several studies have also shown that MC3R variants in both mice and human patients result in the late onset of puberty and abnormal menstrual cycles, as well as a lowered expression of several genes in the circadian rhythm. Despite these observations of how MC3R mutants affect organisms’ phenotype, information regarding the intracellular trafficking of MC3R is unfortunately lacking due to commercially available MC3R antibodies being non-specific in their binding.

This makes the study of MC3R, specifically of its structure and its ligand binding affinity, particularly fascinating as it could very well elucidate some of the mystery that still surround this protein’s function, and I hope I will be able to take steps towards doing so in the coming months. I look forward to continuing improving my skills and pursuing my career both at the Charité Institute and within the ALLODD program.

Perseverance, Hardwork, Deadlines

“What do you want to be when you grow up?” We all get this question several times on the way to becoming an adolescent. Every kid projects themselves in their dream occupation: doctor, engineer, teacher, you name it and you hear some saying “I want to save the world” in an assertive manner, quite heroic. Well, for some of them that bold statement remains as a childish spark and fades away but for others, it even gets stronger and turns into a driving force to make them strive for making the world a better place.
Oh, if you expected the story to go as “… and I was that kid” I must say you´d be quite wrong. I was an ordinary kid with decent dreams, if you had asked me that question at the time, probably you would have heard me saying “a teacher” or “a cook”, but I was always fascinated by the idea of contributing to scientific advancement that will make a remarkable change in people’s lives. This idea flourished as time went by and overpowered my childhood dreams. That’s how I found myself studying chemistry at the university, that’s why I got out of my comfort zone and moved to Belgium later on and last but not least, that's how the course of events made me distort my comfort zone once again, go for an adventure blindly and move to another country and voilà here I am, participating in the ALLODD program, doing a PhD in Spain.

When I first got out of my small world in Turkey, little did I know that it could be quite challenging. Though, what I was feeling was excitement, more than being afraid of the unknown. Not knowing how things are being handled, where to go for certain bureaucratic procedures, not to mention the language issues coming along with not knowing the local language (which is a major problem on its own and yeah English is not always enough to save the day) … When you move to a new country, these are all tough stuff you need to go through every day until you get to the point where you pretty much learn how to get your way.

After living in Belgium for 3 years, give or take, I reached a point where I felt comfortable living there. Though, Belgium still achieves to surprise me every now and then. When it was time to go back to Turkey after my master studies, I was at the point where I needed a fresh start and when I found this great opportunity in Spain, I told myself to go for it. Even though I had never been to Spain before, I was pretty confident that once again, going through all of these struggling & adapting steps of living in another country wouldn’t be scary at all. More challenges, bring ‘em on!
Though there was one ‘tiny’ detail that I didn’t anticipate at the time: the fact that I had forgotten how complicated the visa procedure might be for a non-European person. Although I showed up at the embassy with every possible document that could’ve been asked for (do not underestimate how messy it can get at this stage), it took me 4 months to finally obtain the visa and at the end I bought my ticket from Istanbul to Barcelona, but there was one more obstacle on the way. It was March and it was the coldest time of the last 50 years in Istanbul, snowing like hell. Yeap you guessed it right, I had to postpone my flight due to the unexpected weather conditions. Long story short, I managed to move to Barcelona in mid-March. Shortly after, two new languages were introduced to my brain: Spanish and Catalan and I found myself dealing with the Spanish real estate world and bureaucracy again. Meanwhile I was trying to have a grasp on my PhD project. Two days after the official starting date, I participated in the first ALLODD event in Vienna. I was still trying to make sense of everything since my life changed at a pace faster than I was able to get adapted to.
Though it didn’t stress me out, quite the opposite actually, I liked the feeling of a fresh start.
Fast-forward to June, I was only involved in the program for 2 months and there were 4 conferences awaiting me. There I was as a rookie PhD student preparing presentations and posters without having any results to show, taking part in organizing a conference, getting prepared to welcome all the ALLODD members in Barcelona, the city that I could call home already.

If I had to summarize that period with one word, I’d choose ‘deadlines’. Deadlines was the name of the game basically. It was extremely hectic, but also so satisfactory when I could cross one more item off the to-do list. At the end, after contributing to the organization of a successful event, attending to inspirational conferences where I got the chance to show my work (or let’s say what’s yet to be achieved with my project), meeting new people from all around the world, learning more about different fields, techniques, the feeling I had the most is euphoria.

Things never go as planned, some small tasks that are expected to be completed in a short period of time might fail even at the initial step, hence frustration is inevitable, but it is a part of the job, isn’t it? Nevertheless, the best thing to do is to sit tight and enjoy the ride (without getting too laid back, though).
I am really grateful for where I am now despite all the errors with my calculations, upcoming deadlines and such. I have no clue about what the future holds but whatever that is yet to come, I am impatiently waiting for it and ready to face it and embrace it (Hmm, I wonder if I spoke too soon, well time will tell, I suppose).

I have always enjoyed going to conferences - hearing about others' research, showing my work and participating in scientific discussions and networking events. Still, I didn't realize quite how much planning it takes to organize such an event until June this year when the ALLODD 1st Training School & Networking Meeting took place in Barcelona, Spain. As prof. Xavier Barril’s ALLODD ESR, I had the chance to be part of the organization of the Barcelona meeting events - the Allosterism & Drug Discovery Conference and the ALLODD Training School. Being on the organizational team, I learned all about the little details of scientific meetings and experienced a real organizational process - from having a well-planned program and interesting speakers to thinking about coffee breaks and networking events; from counting numbers and budgets to sending organizational emails to participants. After successfully going through the ups and downs of conference organization, I decided to prepare myself a list of important points on how to plan scientific events. Here are my 7 tips for future conference organization:

1. Always think about the budget. Whatever your budget is, you always have to think about how to fit the event expenses in it. There are many ways to expand a budget but if it is limited you need to make sure to cover as much as possible with it. This always includes expenses for speakers, coffee breaks, conference rooms and spaces and other networking events. If finances are running short you can try to reduce the bills by choosing the basic coffee break offer or inviting speakers who are closer to the conference location. There are many ways to fit into the budget and you should always keep a track of it.
2. Plan the program early on. Conference program planning is definitely not a straightforward process. Now I am seeing it more as a never-ending cycle. First, you think about the theme of the meeting, build the ideas of the talks on diversity and relevance and contact potential speakers. But then things get interesting - people already have other conferences to attend, they are not available or simply not answering their emails. And then you have to rearrange the program on availability again and again. A lot of things can go sideways and finding suitable speakers takes time so the earlier you start planning this the better!
3. Good advertisement is important. Making your event and its program known to as many people as possible will not only increase the interest in it but also the participants’ list and, if applicable, your budget. Having an interesting program and putting it in the announcement of the event is essential! Also, don’t forget to post about it on various and relevant social media.
4. Think about the participants. When you get the advertisement up and going, that’s your cue to concentrate on the participants’ registration. Preparing registration forms, sending confirmation emails and updating the registered on organizational details are good practices that speak well about the conference. Keep in mind that this also helps you keep track of the numbers and set a limit for the number of conference participants, if needed. After the event, it is also valued if you provide attendance certificates to the participants.
5. Booking places has its surprises. As soon as you have a general idea of the conference numbers, it is essential to start booking rooms and conference spaces. Still, you might stumble on unpleasant surprises - the rooms you prefer might be unavailable, the perfect venue for your networking event could be already taken, or there might be problems with air conditioning and space for the coffee breaks. Whatever unplanned things happen along this process, don't stress and be open to alternatives. There is always a way to build a great conference!
6. Don't forget the small details. I cannot even list all the small things you have to keep in mind while organizing a conference but I will mention my favorite ones. Name tags for the participants, gifts for the speakers, water and other amenities; Registration desk, microphones and multimedia in the rooms; A chairperson for every session, poster session organization and networking event planning. You can always think of ways to make the conference experience better, and learning about it comes with practice and even more so from being on the other side as a participant.
7. Enjoy the event. The best advice I can give my future self for conference organization, apart from planning earlier and taking care of the people, is to be present and appreciate the event itself. Probably, mistakes will be made and things may go wrong along the way, but instead of stressing out, fix them as you can, and don’t forget to be proud of your organizational work. On this note, I have to say that being part of the organization of the second ALLODD meeting has been a great experience for me and I am thankful to my supervisor prof. Barril and to prof. Curutchet for including me and ESR4, Özge Ergun, in the planning process - teaching us the essentials of conference organization. Putting in all these efforts made being part of the meeting even sweeter and I cannot wait for the next ALLODD events and planning the next conference.

Happy moments from the ALLODD 1st Training School & Networking Meeting included below!

My PhD experience as part of the ALLODD network and project started some days before my official working day in late January 2022. Just a few days before, I came to explore the city and start adjusting myself to it. The beautiful and romantic atmosphere, the landscapes that the city of Budapest allows you to appreciate are overwhelming. I had never been in this city before, but I felt not so far from home, maybe this was also due to some companion of trip in the first days, but this is another story.

What I would like to focus on is my 6th month period spend here as a PhD student referring to how we perceive time, as someone once said “a year can be the longest or the shortest of your life” (even though we are talking about a half a year this time). The very first working day seems to be so far now but at the same time these full 6 months filled with tasks and events have passed so fast that it doesn’t really feel like half a year. I remember the first day to be caught by the beauty of the building I am currently working in, and the campus surrounding it: I was excited to start this new adventure. Having travelled for several Erasmus projects I took part in, I understood that just after colleagues and network for me the workplace contributes to appreciate what I do. Entering the lab for the first time I felt welcomed, one of my supervisors here introduced me to the group, and my meeting with lab colleagues was making me think glad and happy.

This first impression turned into something real the following days when starting to work. I can say that even though at the start can be a little shy talking with new people everyone showed to be welcoming and available anytime into answer you and dedicate you part of their time and this I really appreciate, and I thank them for it. The next day the work officially started: a project on HDAC8 inhibitors which revealed to be not as easy as predictable. The challenges I believe are those who shape us or shape our thoughts and if we can find a way of learning from that we maybe really could get to reach something good for our own personal and professional growth. Not just challenges but also having the chance to share and learn from more expert figures is something really important and which in my opinion can really drive the scientific progress. This is what I feel getting through the ALLODD network, to be driven somehow in what we do, which of course is not just internationally expressed but also related to the single labs. That said, so the ups and down of research already made their way toward me, but I liked it and I like the challenges, so I started giving myself to it in order to find solutions to the problems and I think several teachings came to my way.

As the first months passed by university events and responsibilities started to approach: exams courses and dates to establish, educational activities, the first meeting in Vienna for the ALLODD project together with some other small tasks, there was little time for stalling! I was thrilled at doing things, completing tasks and assuming responsibilities and meeting other ESRs like me extending our experiences and connections throughout national borders. From my point of view I could particularly appreciate the first ALLODD meeting cause it allowed us to introduce ourselves and while starting creating a network it give us the opportunity to get to know the people taking part in it, have some practical and also psychological training, lectures and experience whose lessons I will never forget and which I believe were really good to introduce as a start point in the first period of our PhD. I liked we had the chance to get to know more about the project, the scheduled events and exchange periods and other Professor and researcher of the ALLODD network, listen to their ideas and experiences, and of course it was also pretty nice to had a walking tour in the city!

Following this just other 3 months have passed filled with new deadlines, new project starting, webinars, reports, the journal clubs, and a new event from the ALLODD was already on the way: the Barcelona workshop. Two days of conference and three spent between presenting our work, training, and experiencing other scientists’ work and realities. Everything was well planned and organized, and we also had the chance to meet and live a little the city together with the other group members. It felt particularly intriguing even to get somehow in touch with other representatives and partners of the consortium through their intervenes and in break times and to deepen some concepts and approaches, and the contrast of previous and new research approach or strategies, all this especially well highlighted in the round tables.

So far, I am so glad to be part of this consortium I am happy I will have the chance to travel and exchange with the industrial world which I never experienced until now and have taken part to these events. It is nice to have the chance to get to know people from different background working together and share experiences and goals towards the common target which is allostery. I hope and I am sure our contribution in this will be important, and that the resources a network and in particular this network can bring will come up useful for understanding and exploring allostery. I am looking forward to other events and opportunity that this founded project will allow us to experience.

On February 2022, I officially joined the MSCA – ITN – ALLODD as an early-stage researcher (ESR) at Merck Healthcare KGaA (Darmstadt, Germany). MSCA – ITN program aims to promote international and interdisciplinary collaboration.
 
As part of this training program, we first met in Vienna in April; you can find some blogposts below. In today´s blogpost, I would like to talk about the 1st training school & Networking meeting which was held in Barcelona. As covid restrictions were slightly less important than in Vienna, this workshop was the opportunity for most of the consortium members to attend in-person.
 
The workshop started with a 2-day conference focusing on allostery in drug discovery with various speakers working both in industry and academia and sharing different perspectives of the topic. The first lecture was held by Dr. Jean-Pierre Changeux, the world-known scientist who described the concept of allostery in 1965. One of Jean-Pierre´s key message was serendipity: an unplanned fortunate discovery (like penicillin). Although, his advice was also to do not misinterpret data, for example receptor dimerization should always be taken in account. I hope I will be as quick-witted as he is at 86 years old !
 
The third day was dedicated to the presentation of our research project. I really enjoy having some more description and going a bit more into details and objectives of each PhD project. Although I am the only ESR working on new biological entities (NBE), the so-called antibodies-derived “nanobodies” gained attendees´ attention.

The industry vs academia perspectives monopolized once again our conversation as we also discussed about our career plan. As I always have been working in industry, become a Scientist in a pharmaceutical company is a natural move for me, I have never thought about changing my career plan. Nevertheless, during our PhD we are going to acquire several skills that will be useful and valuable for a broad range of career plans outside R&D (marketing, venture, …). Furthermore, the application area is neither blocked by our PhD project, Dr. J.P. Changeux studied marine biology and then dedicated all his life to neurobiology and enzymology. My advice will be: learn; read as much as you can, try to deeply understand the concept, do not hesitate to ask questions and share your knowledge.  
 
During this workshop, we also had the opportunity to meet other PhD students working also on allostery. This was very valuable for me as I realized the power of the MSCA ITN program: “Connecting knowledge to grow a network− growing a network to explore/share knowledge” as we said in Vienna. Especially for me, being an industrial PhD student, having many interactions with the academic world and with people all over Europe working on the same topic will for sure empower my work. In addition, as an ESR I must perform three secondments that will not only allow me to adapt to a new country but also to learn new technics and participate to this collaborative project. This workshop was also an overview of the upcoming months as I will spend 3 months in beautiful Barcelona, working on FRET assays with Prof. Carles Curutchet.
 
To conclude, I am delighted to have joined such a collaborative network and I am looking forward to seeing every member of the ALLODD consortium. Next workshop will be co-organized by the University of Strasbourg and Merck Healthcare KGaA, stay tuned.