A Driving Biomedical Project (DBP) involves research in our group that poses a major technical challenge and requires significant further development of our existing software tools, or even entirely new software tools. Below are descriptions of DBPs currently pursued in our group.

DBP1

Continuing our past studies of ribosome structure and function, we seek to solve structures of the bacterial ribosome docking to a protein chaperone called a trigger factor. The structure of the complex is to be solved employing new Molecular Dynamics Flexible Fitting (MDFF) features such as tools dealing with flexible regions of an EM map. By using structure predictions as starting points for MDFF simulations, an innovative feature in the future MDFF suite currently under development, the Center also seeks to resolve structures of eukaryotic ribosome systems from yeast and Drosophila melanogaster. The Center scientists will employ for this purpose GPU-accelerated algorithms from NAMD, e.g., for the study of signal transduction in the ribosome.

Collaborating Investigators: Klaus Schulten, UIUC; Joachim Frank, Columbia U. and HHMI; Kurt Fredrick, Ohio State U.; Ruben L. Gonzalez, Jr., Columbia U.; Taekjip Ha, UIUC and HHMI; Roland Beckmann, U. Munich.

Funding: HHMI Award, 2010-2015 (Frank); NIH R01-GM029169, 2010-2012 (Frank); NIH R01- GM055440, 2009-2014 (Frank); NIH R01-GM072528, 2005-2014 (Fredrick); NIH R01-GM084288, 2008-2013 (Gonzalez); NIH R01-GM090126, 2010-2014 (Gonzalez); NSF PHY-0822613, 2008-2013 (Ha).

DBP2

The goal of this project is to describe in atomic detail how biological membranes control the binding and activity of blood coagulation proteins by dynamically changing their lipid compositions, and to characterize specific lipid-protein interactions and binding sites on the proteins that might serve as potential novel drug targets. The studies will rely on software development underway for a Membrane Environment Modeler tool, on faster simulation methods from NAMD, and on the development of a Brownian Mover tool.

Collaborating Investigators: Emad Tajkhorshid, UIUC; James H. Morrissey, UIUC; Chad M. Rienstra, UIUC; Stephen G. Sligar, UIUC.

Funding: NIH T32-GM007283, 2007-2012 (Morrissey); NIH R01-HL047014, 2011-2015 (Morrissey); NIH R01-HL103999, 2010-2015 (Morrissey and Rienstra); NIH R01-GM079530, 2007-2012 (Rienstra); NIH R37-GM031756, 2009-2013 (Sligar); NIH R01-GM086749, 2009-2014 (Tajkhorshid); NIH R01-GM067887, 2003-2011 (Tajkhorshid).

DBP3

The Center will investigate physiological processes at the cellular level with leading experimental researchers. Stochastic effects that result in cell-to-cell differences will be modeled to understand how pathogens use persistence to evade host immunity. Simulating large biochemical reaction networks will drive the development of software being developed for whole-cell simulation. Computational models of small eukaryotic cells and cell division in bacteria will require GPU acceleration (to be developed in the whole-cell simulation software). The whole-cell studies will be complemented by MD simulations at the organelle scale, namely of the chromatophore in purple bacteria, a simple bioenergetic pseudo-organelle.

Collaborating Investigators: Zaida Luthey-Schulten, UIUC; Wolfgang Baumeister, Max Planck Inst. of Biochem.; C. Neil Hunter, U. of Sheffield, U.K.; Nathan Price, Inst. Systems Biology and U. of Washington; Jie Xiao, Johns Hopkins U.

Funding: NIH/NCI K99/R00 2008-2012 (Price); DOE DE-FG02-10ER6510, 2010-2013 (Luthey- Schulten, Price, Woese); NSF EAGER 1019000, 2010-2012 (Xiao); NIH R01-GM086447-01A2, 2011-2016 (Xiao).

DBP4

The Center will investigate the potential of a DNA nanopore sensor for sequencing human DNA at ultra-low cost. The sensor will be based on the bacterial membrane protein MspA. The Center will also work on increasing the fidelity of solid-state nanopore sensors through investigation of a new kind of graphene-based nanopore, offering ultimate resolution in detecting DNA base pairs. The optimization of nanosensors will drive development of Brownian dynamics software and hybrid quantum-classical MD simulations furnished in NAMD.

Collaborating Investigators: Alek Aksimentiev and Klaus Schulten, UIUC; Rashid Bashir, UIUC; Jens Gundlach, U. Washington; Gregory Timp, U. Notre Dame; Meni Wanunu, Northeastern U.

Funding: NIH R21-CA155863-01, 2011-2012 (Bashir); NIH R01-HG005115, 2011-2013 (Gundlach); NIH R01-HG006321, 2011-2014 (Wanunu).

DBP5

The effectiveness of antiviral drugs is continually challenged by the emergence of new drug-resistant strains. An emerging opportunity to develop new types of drugs is through inhibition of virus cell entry. The molecular mechanisms of the infection process for a model animal virus, poliovirus, will be studied in atomic detail utilizing Center technologies, including MDFF and the highly mobile membrane mimetic (HMMM) model being developed as part of a Cell Biology Software suite, as well as coarse-grained simulation and enhanced sampling capabilities developed in NAMD. The researchers seek to determine complete atomic structures of the poliovirus cell entry intermediates by MDFF and of the virus-membrane complex involved in membrane penetration by HMMM.

Collaborating Investigators: Klaus Schulten, UIUC; James Hogle, Harvard U.; Peter Ortoleva, Indiana U.

Funding: NIH R01-AI20566, 2008-2013 (Hogle); NIH R01-GM085578, 2008-2012 (Hogle); NSF CHE-0832651, 2008-2013 (Ortoleva).

DBP6

Integrins are receptors on the cell surface, linking the cell to its surrounding environment. Due to their broad biological and therapeutic significance, integrins have been avidly investigated. Jointly with leading experimentalists, we seek to determine the molecular basis of integrin bidirectional (outside-in and inside-out) transmembrane signal transduction. The Center will utilize QM/MM methods, enhanced sampling techniques and faster simulation methods, all from NAMD.

Collaborating Investigators: Klaus Schulten, UIUC; Timothy A. Springer, Harvard U.; Taekjip Ha, UIUC and HHMI.

Funding: NIH R01-AI072765, 1988-2011 (Springer); NIH P01-HL048675, 1997-2011 (Springer); NIH P01-HL103526, 2011-2012 (Springer); HHMI Award, 2005-2015 (Ha); NSF PHY-0822613, 2008-2013 (Ha, Schulten).

DBP7

Membrane transporters mediate key processes in living cells such as termination of neural signals in the central nervous system, absorption of nutrients in the digestive tract, secretion of waste materials and ions in the kidneys, and development of drug re- sistance in cancer cells. Conformational changes of various forms and magnitudes, ranging from localized, gate-like motions to large-scale, global structural transitions, are at the heart of the function of membrane transporters. Characterizing these conformational changes has proven extremely challenging using experimental techniques. Molecular dynamics simulations offer an alternative means to resolve the conformational changes. The long simulation timescales required and extreme need of sampling and analysis challenge development in NAMD and VMD.

Collaborating Investigators: Emad Tajkhorshid, UIUC; Hassane Mchaourab, Vanderbilt U.; Robert Nakamoto, U. Virginia; Da-Neng Wang, New York U.; Harel Weinstein, Cornell U.

Funding: NIH R01-GM086749, 2009-2014 (Tajkhorshid); NIH R01-GM067887, 2007-2011 (Tajkhorshid); NIH U54-GM087519, 2010-2015 (Mchaourab, Nakamoto, Weinstein and Tajkhorshid); NIH R01-MH083840, 2008-2013 (Wang); NIH R01-DK053973, 1998-2011 (Wang).