Additional recruitment to the Doctoral School of Natural Sciences  beyond the limit of places

Project description:    

Enzymes are indispensable for the function of every living cell, catalyzing the efficient execution of a vast number of concurrent chemical reactions. These reactions occur in enzymes’ active sites that are either exposed on the protein surface or, very frequently, buried deep inside its core. The access of substrates and the release of reaction products via molecular tunnels is essential for the function of these buried sites. Aside from enabling efficient catalysis in these enzymes, tunnels constitute a structural basis of various regulatory mechanisms critical to the living cell. Despite their utmost importance, tunnels are rarely explicitly considered in protein research due to obtrusive challenges in their identification arising from their often fleeting nature. The ensuing knowledge gap precludes linking tunnel mutations to pathologies, targeting the tunnels during drug discovery, and designing proficient enzymes with buried active sites.

The proposed project aims at developing machine learning models capable of predicting functional tunnels from the static protein structures building on top of the in-house dataset of high-throughput adaptive sampling molecular dynamics simulations of a diverse set of enzymes in which ensembles of relevant transport tunnels were delineated. Such a model would ultimately allow us to benefit from the availability of high-quality structural models for millions of proteins, enabling accurate predictions of functionally relevant transport tunnels.

The available dataset containing over 90 million tunnels with about 2.4 million migrating water molecules identified in the simulations of 40 different enzymes will be curated to provide optimal training data. For actual model development, we plan to benefit from the recently developed protocol for cryptic pocket prediction, which has shown that models based on geometric vector perceptron graph neural networks as well as 3D convolutional neural networks, can be successfully trained for accurate detection of viable cryptic pockets using data from molecular dynamics simulations containing less than 1 million of pocket cases. Given that opening molecular gates of transient tunnels can be seen as a similar task, albeit with the added complexity of tunnel length, spanning larger part of protein structures, and the possible presence of multiple gates, we presume that a similar approach can also be developed for transient tunnel prediction.

Additionally, we will analyze the predictive capabilities of derived models on well-characterized enzyme families to expose potential limitations in their applicability. We also plan to contrast the predictions based on the sampled tunnel geometries and their utilization for water transport with the actual use of these tunnels by cognate ligand using t-random accelerated simulations. Finally, we will employ the best-performing model to disclose the presence of functional transient tunnels in biotechnologically relevant hydrolytic enzymes and the humane proteome.

Overall, the project aims to help transform the current approaches for the analysis of enzymes with buried sites and to deliver fundamental insights necessary for the construction and optimization of tunnels in designed enzymes, targeting the tunnels by inhibitors or engineering inhibitors with high residence times in the targeted active sites for drug development, as well as revealing the effects of distal mutations in tunnels on pathology development. 

Principal investigator: prof. UAM dr hab. Jan Berezovsky - NCN 2023/50/O/NZ2/00122 

Recruitment:

Selection Committeee       

Recruitment fee

The recruitment fee is 75 EUR.

Form of the selection procedure

Two-stage procedure.

Language of the selection procedure, including interviews:

Polish or English language. 

Required documents:

 1.        Candidates who have obtained the necessary education outside the territory of the Republic of Poland, shall additionally submit:

1)    a photocopy of a document which confirms their education, certified to be a true copy of the original document, i.e. a diploma with a supplement confirming completion of first cycle studies (Bachelor degree) and a diploma with a supplement confirming completion of second cycle studies (Master degree, MSc, MA) in the original language and in a certified translation into English or into Polish,

            2)    a photocopy of their passport. 

 Evaluation criteria

 1)    the grade awarded for the diploma of the second cycle studies or single cycle five year master’s studies - maximum 10 points; in the case of candidates who seek admission on the basis of superior academic achievements ("Pearls of Science") - 10 points;

 2)    evaluation of the candidate's scientific activity and scientific achievements; the candidate indicates for evaluation up to three documented scientific achievements, in accordance with the achievement criteria adopted by the selection committee for a given discipline - maximum 15 points;

 3)    evaluation of the candidate's other documented activity, based on a maximum of three achievements consistent with the achievement criteria adopted by the selection committee for a given discipline - maximum 5 points

 4)    the result of the interview, with the scope of the interview including:

 a)    the candidate's knowledge and competencies relevant to the planned research and appropriate to the indicated scientific discipline,

 b)    elements of research methodology appropriate for the discipline indicated.

 No more than 50 points can be awarded for the interview; the maximum duration of the interview is 30 minutes.

 5)    evaluation of the research project prepared and submitted for assessment to the selection committee (maximum 20 points), with particular emphasis on:

 a)    the ability to formulate the research objective and present the research problem;

 b)    research idea and the ability to propose a solution;

 c)    methodology appropriate to the discipline indicated;

          d)    knowledge of the state of research with a basic bibliography. 

Condition of admission to the Doctoral School 

Education Program

Education at the doctoral school lasts 8 semesters. Education at the Doctoral School  is offered on the basis of a framework curriculum and an individual research plan and ends with the submission of a doctoral dissertation.

The framework curriculum at the doctoral school includes a catalogue of modules of compulsory classes, elective compulsory classes and optional classes. It also:

1)    defines their schedule

2)    defines the way in which the classes are taught

3)    defines how learning outcomes are verified.

Education begins on 1st October, 2024.

Supervisors

A doctoral student works under the supervision of a supervisor or supervisors, or a supervisor and auxiliary supervisor, who will be appointed by the Deputy Rector at the request of a doctoral student (within 3 months of the start of his or her studies at the Doctoral School).

Scholarships

Doctoral student receives a scholarship PLN 5000 gross gross for the first two years of studies (before the mid-term evaluation) and PLN 6000 gross gross  for two years following mid-term evaluation (maximum 4 years).

Rules of admission to doctoral schools of Adam Mickiewicz University, Poznań in the academic year 2024/2025, Appendix to Resolution No. 478/2023/2024 of UAM Senate of 18th  December, 2023.