Frustration and disorder in proteins

Native states of proteins are considered to be minimally frustrated. Folding, however, conflicts with adaptation. Based on the energy landscape theory, sub-optimal interactions increase local frustration, similarly to spin glasses, and thus enhance functional variability. Disordered proteins occupy a broad range of their energy landscapes. Templated folding upon interacting with a biological partner can decrease the frustration of disordered proteins. The resulted bound state structures however, differ from normal protein complexes and contain a high density of sub-optimal contacts. Such frustration serves as a basis of most regulatory points in cellular pathways.
I'm interested in the relationship between frustration patterns and specificity. I develop computational approaches to link frustration to functional variability of protein complexes. I'm in particular interested in the origin of selectivity in a frustrated complex and the physical basis of controlled promiscuity.


Fuzziness in protein interactions

Protein function is traditionally described by a deterministic structure-function model, which fails to explain cellular adaptation. Understanding biological activities under stochastic environment, requires more complex models, which can relate population shifts in dynamic conformational ensembles to changes in function. I apply a many-valued or fuzzy logic to establish a stochastic structure-function paradigm.
As a model system, I use interactions of disordered proteins, which exhibit fuzzy binding. These proteins use different binding modes and contact patterns with different partners or under different cellular contexts. I aim to elucidate the sequence-codes of fuzzy binding and how they are influenced by different cellular conditions. I plan to design a fuzzy inference system, which can be used to control the behavior of disordered proteins.


Protein phase separation

Cell biology has been revolutionized by the discovery that some proteins are capable to undergo liquid-liquid phase separation and form non-membrane bound organelles in cells. Some of these droplets are functional, but the biological roles of these higher-order assemblies in most cases are rather enigmatic. Protein liquid droplets exhibit weak, yet specific interactions, similar to those in fuzzy complexes. Based on this, I develop sequence-based prediction methods to identify proteins, which are capable to drive protein phase separation. Some proteins may form droplets via context-dependent binding to a set of specific partners. I aim to elucidate the biophysical principles and sequence codes of droplet-client proteins.

Familial mutations, aging or cellular conditions may initiate the conversion of droplets to fibrils leading to a variety of pathologies (such as amyotrophic lateral sclerosis). I study those factors, which promote such aggregation pathways with an aim to predict mutation hot-spots.


Entropy-based drug discovery

Understanding fuzzy binding may open novel avenues for drug discovery. I work on developing quantitative models for entropy-controlled specificity of disordered targets, which can be cross-validated by experimental data. I'm in particular interested in unsuccessful cancer targets, and proteins undergoing phase separation. I also aim to establish contact libraries for disordered targets for small molecule optimisations.

2020e PhD thesis Multiscale approaches to conformational heterogeneity in enzymatic catalysis (Gyula Hoffka)
2020e PhD thesis Conformational heterogeneity and dynamics in enzymatic catalysis and evolution (Fruzsina Zsolyomi – bioinformatician at Turbine.AI , Budapest)
2020e PhD thesis Dynamic interaction motifs in antiviral response (Norbert Duro – team leader at Chinoin Pharmaceuticals)
2019 PhD thesis Nanny model for intrinsically disordered proteins (Rashmi Sharma – PD at Weizmann Institute of Science, Israel)
2019 MSc thesis Amino Acid Sequence-Based Protein Dynamic Analysis of Vertebrate Thrombins (Balazs Kunkli – PhD University of Debrecen)
2015 MSc thesis Dynamic protein interaction motifs in rational drug design (Zsolt Raduly – PhD University of Debrecen)
2015 MSc thesis The role of protein dynamics in enzyme evolution (Viktor Ambrus – PhD University of Debrecen)
2015 MSc thesis Molecular mechanisms of viral motifs (Norbert Duro – PhD University of Debrecen , team leader at Chinoin Pharmaceuticals)
2014 MSc thesis The role of fuzziness in viral protein complexes (Sandor Erdei – research assistant, University of Debrecen)
2013 MSc thesis Studying enzyme evolution by computer simulations (Aniko Labas – PhD Budapest University of Technology and Economy)
2013 BSc thesis Characteristic linear motifs associated with cancer (Eniko Juhos)
2007-2011 PhD thesis Dynamic boundaries in hybrid QM/MM simulations (Ivan Solt – leader ChemAxon, Hungary)
2007-2011 PhD thesis Investigation of complex systems by hybrid QM/MM molecular dynamics methods (Letif Mones – postdoc at Engineering Laboratory, University of Cambridge UK, instructor at Department of Mathematics, University of Warwick UK, staff researcher at Invenia Labs, Cambridge UK)
2011 MSc thesis Analysis of dynamic properties in protein evolution (Rita Pancsa – PhD at VIB Brussels, postdoc at LMB MRC Cambridge, PI at Institute of Enzymology, Budapest)
2011 BSc thesis Rational enzyme design based on Kemp elimination (Aniko Labas – PhD Budapest University of Technology and Economy)
2011 BSc thesis Interpretation of enzymatic catalysis using simulation methods (Eszter Szabo – MSc Budapest University of Technology and Economy)
2007-2009 PhD The role of disordered tails in DNA recognition (Agnes Toth-Petroczy – postdoc at Harvard Medical School, PI at Max Planck Cell Biology and Genetics Institute, Dresden, Germany)
2008 BSc thesis The role of intrinsically disordered proteins in biochemistry (Rita Pancsa – PhD at VIB Brussels, postdoc at LMB MRC Cambridge, PI at Institute of Enzymology, Budapest)
2007 MSc thesis Molecular recognition of uracil-containing DNA (Agnes Toth-Petroczy – postdoc at Harvard Medical School, PI at Max Planck Cell Biology and Genetics Institute, Dresden, Germany)
2006 MSc thesis The role of metal ions in BamHI catalysis methods (Letif Mones – postdoc at Engineering Laboratory, University of Cambridge UK, instructor at Department of Mathematics, University of Warwick UK, staff researcher at Invenia Labs, Cambridge UK)
2005 MSc thesis The role of divalent metal ions in specific DNA recognition (Ivan Solt – leader ChemAxon, Hungary)