JansPage

From PropKaWiki

Research Summary

My work is primarily in the area of biocomputational chemistry – at the intersection between quantum chemistry and structural biology/bioinformatics. My work involves, in roughly equal parts, software development and applications to biochemistry. More specifically my research program has three main foci:
(1) Development and application of the PROPKA program to the rational design of more stable proteins.
(2) Development of quantum chemical and QM/MM methods and application to enzyme catalysis.
(3) Extension of PROPKA to protein-ligand binding and drug design.

A complete list of publications can be found here

PROPKA and Protein Stability

The main focus of my work is in protein design, and is based on the program PROPKA, which can rapidly and accurately predict the pH-dependent physicochemical properties of a protein, such as stability and activity. The method is based on a completely novel theory of electrostatic interactions within proteins, which was derived based on quantum mechanical calculations of proteins. It is among the most accurate and certainly the fastest of such programs currently available, and is used extensively by the scientific community:

PROPKA webserver

• PROPKA is available as a web service (the first of its kind when it was launched in early 2005), and this web server receives about 1500 page views every month.
• The Proteins paper describing PROPKA appeared in December 2005 and has already been cited more than 333 times. Last time I checked (Sepctember 2011) it was the second most cited Proteins paper published since 2000.
• PROPKA is quickly becoming the de facto standard for preparing and analyzing protein structures for simulations, and has been included in other popular protein manipulation programs such as PDB2PQR, VEGA-ZZ, and WebPDB.
The applications of a program like PROPKA for protein design are compelling and profound, and I published a proof-of-concept study on xylanases in Biochemistry in 2007. Further development and applications are ongoing in several supported projects:

animation

The project Computational Design of Stable Enzymes is supported by the DSF through the NABIIT program with 7,500,000 DKK and involves Mats Olsson and Michal Rostkowski (postdocs) who are extending PROPKA into a tool for designing stable enzymes, and Pernille Galberg and Søs Torpenholt (Ph.D. students) who are performing the experimental validation. The project is headed by myself and involves Leila Lo Leggio and Ulla Christensen from KIKU, and includes participants from Novozymes, RUC, and University of British Colombia. On the right you can see a short animated presentation of this work.

The ERUDESP Project

The project Development of Electrochemical Reactors Using Dehydrogenases for Enantiopure Synthon Preparations (ERUDESP) is supported by the EU and involves Chresten Søndergaard (postdoc) who will provide further PROPKA development and rational design support. The project is headed by Saarland University, and includes participants from 8 research groups (including Leila Lo Leggio’s) from Germany, France, and Turkey.

The project Protein Design: Development of molecular biology and bioinformatics tools (link) is supported by FTP and is headed by Jakob Winther (Biology) and includes Leila Lo Leggio, Thomas Hamelryck (Bioinformatics Center), Kaj Frank Jensen (Biology) and Jesper Ferkinghoff-Borg (DTU) as well as myself.

QM/MM and Enzyme Catalysis

Much of my early work has focused the development of QM/MM methods where part of the system, e.g. enzymatic active site, is described by quantum mechanics (QM) while the rest of the system is described by molecular mechanics (MM). Casper Steinmann (Ph.D. student) and I am now collaborating with Dmitri Fedorov at the National Institute for Advanced Industrial Science in Japan and Kazuo Kitaura at Kyoto University on combining QM/MM and linear scaling QM methods in the GAMESS-US program.

The main application of the QM/MM methods will be in the rational design enzymes with new substrate specificity. This entails the prediction of mutations that will allow the new substrate to bind, using both QM/MM and conventional docking software and ultimately the PROPKA method (next section), and predicting the catalytic efficiency of the mutant protein on the new substrate. Further development and applications are ongoing in the following supported projects:

This work also forms the basis of the EU proposal entitled In Silico Rational Engineering of Novel Enzymes (IRENE). The project is headed by University of Trieste, and includes participants from 11 research groups (including Novozymes) from Italy, Sweden, Denmark, The Netherlands, Uzbekistan, and Russia.

The project Enzyme design: shaping substrate specificity using computational chemistry and novel screening methodology is supported by FTP and is lead by Martin Willemoes (Biology), and included Jakob Winther (Biology) and myself.

Designing new substrate specificity is also a goal of the fuel cell project mentioned in the previous section.

PROPKA, Protein-Ligand Binding, and Drug Design

The PROPKA method has recently been extended to include the effect of ligands to predict the pH-dependence of protein-ligand binding and the electrostatic part of the binding energy (PROPKA 2.0).

The project Modeling pH effects in rational drug design was supported by the EU International Reintegration Program and funded David Rogers (postdoc) to work on the title project.

The project Rational design of ultra sensitive nanowire based biosensors for proteomics is supported by FTP and involves Luca De Vico (postdoc) who uses PROPKA to predict the change in charge upon binding of ligands to proteins attached to nanowires. Luca is currently working on interfaces with mesoscale models to predict the change in nano-wire conductance measured by our experimental collaborators. The project is headed by Jesper Nygård (NBI) and includes Karen Martinez (Nano-Science Center).

Molecular Modeling in Chemical Education

The Book

screencast from my blog

I am also very interested in incorporating molecular modeling into chemical education:
* I have written a book called Molecular Modeling Basics published by CRC Press.
* I consult with the developers of the software package Avogadro on issues related to GAMESS and education.
* I make screencasts for educational use. You can see an example on the right, and many more on my blog.
* I create Jmol applications for educational use, like this one, which animates rotational and vibrational energy states in water.
* I run a blog called Molecular Modeling Basics aimed at getting started with molecular modeling and using it in teaching.