Jozef Adam Liwo

Statement of Research

Most Significant Research Accomplishments

My research interests concern the development and application of methods of computational chemistry to study study the structure and dynamics of biomolecules and biomolecular processes and to analyze physicochemical data. My most significant research accomplishment is the development, during the last 15 years, of a united-residue model of polypeptide chain (UNRES) [1], which enables both physics-based protein-structure prediction and millisecond-scale simulations of the dynamics of large protein systems. I have done this work in cooperation with Prof. Harold A. Scheraga, Cornell University. UNRES is publily available from a number od server, e.g., at Cornell University (http://cbsu.tc.cornell.edu/software/protarch/index.htm), Academic Computer Center in Gdansk, Poland (http://www.task.gda.pl/nauka/software/protarch/index.html), and Faculty of Chemistry, University of Gdansk (http://www.chem.univ.gda.pl/~adam/Downloads/index.html).

In the UNRES model [1] a polypeptide chain is represented as a sequence of $\alpha$-carbon (C$^\alpha$) atoms with united peptide groups (p) located in the middle between two consecutive C$^\alpha$'s each and united side chains (SC) attached to the respective C$^\alpha$'s. In contrast to most united-residue force fields which are largely knowledge-based potentials, UNRES was carefully derived based on the physics of interactions, as a cluster-cumulant expansion of the effective free energy of a protein plus the surrounding solvent, in which the secondary degrees of freedom had been averaged out. The force field has been optimized for foldability based on the energy-landscape theory; for this purpose, we developed a novel method [2], which makes use of the hierarchical structure of protein energy landscape. The optimized force field is able to predict the structure of moderately-sized proteins without using any information from structural databases, as judged in the Community Wide Experiments of Critical Assessment of Techniques for Protein Structure Prediction (CASP) [3]. We recently implemented a mesoscopic molecular dynamics algorithm to UNRES [4]. We found that UNRES in connection with MD is capable of simulating, starting from an arbitrary conformation, the folding pathways of proteins with 75-100 amino-acid residues on a single processor in a few hours on average; when massively parallel computer systems are used proteins with size more than 1000 residues can be treated.

For the research described above, I received 4 research grants and 4 supplementary grants to support my graduate students from the Polish government (since 1996) and, together with Professor Harold A. Scheraga, a collaborative research FIRCA grant in years 1999-2004, in which I acted as the Foreign PI.

Other Research Accomplishments

I have also done and am doing successful work in the following subjects; one most significant reference is cited per each item for illustration:

  1. Conformational studies of small peptides in relation to early stages of protein folding [5] (current work).

  2. Conformational studies of bioactive peptides [6] (current work). As a follow-up of this research, I was one of the key developer of the publicly available ECEPPAK package for global conformational analysis of polypeptides (available from, e.g., http://cbsu.tc.cornell.edu/software/eceppak/index.htm and http://www.task.gda.pl/nauka/software/eceppak/index.html)

  3. Development of an algorithm for determining conformational ensembles of flexible peptides from NMR data with the aid of MD and MC simulations [7] (current work). This work resulted in publicly available ANALYZE software (available from, e.g., http://cbsu.tc.cornell.edu/software/analyze/index.htm and http://www.task.gda.pl/nauka/software/analyze/index.html)

  4. Theoretical studies of hydrophobic association [8] (current work).

  5. Theoretical studies of acidic-basic properties of organic molecules [9] (current work).

  6. Theoretical studies of the interplay between peptide and protein conformation and protonation state [10] (current work).

  7. Investigation of reactive oxygen species generation and their interactions with organic compounds in relation to the peroxidating properties of anthracyclne-based anti-cancer drugs [11] (current work).

  8. Theoretical studies of gelsolin-lipid interactions [12] (past work).

  9. Theoretical modeling of enzymatic reactions [13] (past work).

  10. Development of algorithms for QSAR [14] (past work).

  11. Development of algorithms for determination of stoichiometry and equilibrium constants from physicochemical data [15] (past work). The software is publicly available from the server at the Faculty of Chemistry, University of Gdansk (http://www.chem.univ.gda.pl/~adam/Downloads/index.html)

Research Plan

Further development and extensions of UNRES

In the immediate future I will continue the work on parameterization of UNRES to reproduce protein structural, thermodynamic, and kinetic data with the use of more training proteins of diverse structural classes and quantitative thermodynamical and kinetical characteristics of the effect of mutation (free energies of folding, the $\Phi$ values, etc.) to evaluate the force field. In about 6 months from now, I plan to start extending UNRES to include variable ionization state of the acidic and basic side chains, which will enable us to run constant-pH calculations, and to parameterize UNRES for membrane environment. A more far-sighted research task is to extend the UNRES approach to nucleic acids. My other future plans in this directions are to extend UNRES to treat peptide nucleic acids (PNA), polysaccharides, and other biologically important macromolecules and molecular assemblies.

References

1
A. Liwo, C. Czaplewski, S. O\ldziej, A.V. Rojas, R. Kazmierkiewicz, M. Makowski, R.K. Murarka, H.A. Scheraga.
- Simulation of protein structure and dynamics with the coarse-grained UNRES force field.
In G. Voth, editor, Coarse-Graining of Condensed Phase and Biomolecular Systems, chapter 8, 1391-1411, 2008, (2008).

2
A. Liwo, M. Khalili, C. Czaplewski, S. Kalinowski, S. O\ldziej, K. Wachucik, H.A. Scheraga, - Modification and optimization of the united-residue (UNRES) potential energy function for canonical simulations. I. Temperature dependence of the effective energy function and tests of the optimization method with single training proteins, J. Phys. Chem. B, 111, 260-285 (2007).

3
S. O\ldziej, C. Czaplewski, A. Liwo, M. Chinchio, M. Nanias, J.A. Vila, M. Khalili, Y.A. Arnautova, A. Jagielska, M. Makowski, H.D. Schafroth, R. Kazmierkiewicz, D.R. Ripoll, J. Pillardy, J.A. Saunders, Y.K. Kang, K.D. Gibson, H.A. Scheraga, - Physics-based protein-structure prediction using a hierarchical protocol based on the UNRES force field: Assessment in two blind tests, Proc. Natl. Acad. Sci. U.S.A., 102, 7547-7552 (2005).

4
A. Liwo, M. Khalili, H.A. Scheraga, - Ab initio simulations of protein-folding pathways by molecular dynamics with the united-residue model of polypeptide chains, Proc. Natl. Acad. Sci. U.S.A., 102, 2362-2367 (2005).

5
J. Makowska, S. Rodziewicz-Motowid\lo, K. Baginska, J.A. Vila, A. Liwo, L. Chmurzynski, H.A. Scheraga, - Polyproline II conformation is one of many local conformational states and is not an overall conformation of unfolded peptides and proteins, Proc. Natl. Acad. Sci. USA, 103, 1744-1749 (2006).

6
A. Liwo, A. Tempczyk, S. O\ldziej, M.D. Shenderovich, V.J. Hruby, S. Talluri, J. Ciarkowski, F. Kasprzykowski, L. Lankiewicz, Z. Grzonka, - Exploration of the conformational space of oxytocin and arginine-vasopressin using the electrostatically-driven Monte Carlo and molecular dynamics methods, Biopolymers, 38, 157-175 (1996).

7
M. Groth, J. Malicka, C. Czaplewski, S. O\ldziej, L. \Lankiewicz, W. Wiczk, A. Liwo, - Maximum entropy approach to the determination of solution conformation of flexible polypeptides by global conformational analysis and NMR spectroscopy - application to DNS$^1$-c-[D-A$_2$bu$^2$,Trp$^4$,Leu$^5$]enkephalin and DNS$^1$-c-[D-A$_2$bu$^2$, Trp$^4$, D-Leu$^5$]enkephalin, J. Biomol. NMR, 4, 315-330 (1999).

8
C. Czaplewski, A. Liwo, D.R. Ripoll, H.A. Scheraga, - Molecular origin of anticooperativity in hydrophobic association, J. Phys. Chem. B, 109, 8108-8119 (2005).

9
J. Makowska, M. Makowski, A. Gie\ldon, A. Liwo, L. Chmurzynski, - Theoretical calculations of heteroconjugation equilibrium constants in systems moldeling acid-base interactions in side chains of biomolecules using the potential of mean force, J. Phys. Chem. B, 108, 12222-12230 (2004).

10
D.R. Ripoll, Y.N. Vorobjev, A. Liwo, J.A. Vila, H.A. Scheraga, - Coupling between folding and ionization equilibria. Effects of pH on the conformational preferences of polypeptides, J. Mol. Biol., 264, 770-783 (1996).

11
M. Bobrowski, A. Liwo, S. O\ldziej, D. Jeziorek, T. Ossowski, - CAS MCSCF/CAS MCQDPT2 study of the mechanism of singlet-oxygen addition to 1,3-butadiene and benzene, J. Am. Chem. Soc., 122, 8112-8119 (2000).

12
I. Liepina, C. Czaplewski, P. Janmey, A. Liwo, - Molecular dynamics study of a gelsolin-derived peptide binding to a lipid bilayer containing phosphatidylinositol 4,5-bisphospate, Biopolymers, 71, 49-70 (2003).

13
M. Tarnowska, S. O\ldziej, A. Liwo, P. Kania, F. Kasprzykowski, Z. Grzonka, - MNDO study of the mechanism of the inhibition of cysteine proteinases by diazomethyl ketones, Eur. Biophys. J., 21, 217-222 (992).

14
A. Liwo, M. Tarnowska, Z. Grzonka, A. Tempczyk, - Modified Free-Wilson method for the analysis of biological activity data, Comput. Chem., 16, 1-9 (1992).

15
J. Kostrowicki, A. Liwo, - A general method for the determination of the stoichiometry of unknown species in multicomponent systems from physicochemical measurements, Comput. Chem., 11, 195-210 (1987).