The goal of this project is to improve the accuracy of molecular dynamics (MD) simulations for studying the structure and dynamics of intrinsically disordered proteins (IDPs). Intrinsically disordered proteins (IDPs) make up about a third of the proteins found in eukaryotic cells (cells of more complex organisms than bacteria), and are involved in many essential cellular processes, but as their name implies, their structures are not well defined. In this project, the investigators will develop force fields, the physics based laws that describe how atoms interact with each other, that can be used for IDPs in MD simulations. This work will contribute to understanding how IDPs contribute to the machinery of life. New MD force field parameters will be made publicly available such that others can use them in their simulations. The interdisciplinary research will carried out by three graduate students who will gather expertise in MD, biophysics, physical and organic chemistry, and a variety of spectroscopic techniques. The project will foster an international collaboration among the laboratories of Profs. Urbanc (PI) and Schweitzer-Stenner (Co-PI) at Drexel University in Philadelphia and Harald Schwalbe at the Johann Wolfgang Goethe University in Frankfurt/Germany. PI and Co-PI will organize summer workshops on MD simulations of unfolded peptides at Drexel University and an effort will be made to attract students and faculty targeting underrepresented minorities from neighboring institutions to attend this event. The research outcomes will be featured through the annual Kaczmarczik Day event, which offers demonstrations of research conducted at the Physics and Chemistry Departments at Drexel University to the general public, mostly high school students from the local Philadelphia area.
Experimental research on unfolded peptides demonstrate that for most amino acid residues in water the backbone dihedral angles are restricted to two predominant regions in Ramachandran plot corresponding to polyproline II (pPII) and beta-strand. Of all amino acids, alanine shows the highest pPII propensity, which is important in the context of molecular dynamics (MD) force field development that routinely uses alanine-based short peptides as reference systems. Current MD force fields consistently fail to reproduce the high pPII content of alanine-based short peptides observed in vitro. The PIs and collaborators have acquired multiple experimental data for most naturally occurring guest residue x in GxG (G-glycine, x-all amino acids other than Q, G, P and W) peptides in water, which allowed them to uniquely determine residue-specific intrinsic conformational ensembles. This proposal will utilize this comprehensive set of experimental data to test the existing MD force fields and water models with respect to their ability to reproduce the conformational propensities of guest residues x in GxG peptides in water (Aim 1); derive a new parameterization of the existing MD force field, AMBER ff99SB, and combine it with the water model that best captures the intrinsic conformational propensities of guest residues x in GxG peptides to obtain the new force field AMBER ff99SB EXP-GxG (Aim 2); and conduct a systematic five-step assessment of the resulting AMBER ff99SB EXP-GxG force field that will test its transferability to longer unfolded peptides and its ability to capture protein folding and protein self-assembly into soluble protein oligomers (Aim 3). These advances in MD force field development will improve predictions of MD simulations of IDPs.
This award is jointly funded by the Molecular Biophysics Cluster of the Division of Cellular and Molecular Biosciences and the Chemical Theory, Models and Computational Methods Program in the Chemistry Division.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
