Ions are essential components of biomolecular systems. One third of all proteins contain metal ions as integral parts for structural or functiona purposes. Binding of negatively charged phosphate groups is ubiquitously involved in regulation, signal transduction and various other processes. Whereas is a plethora of experimental structural and thermodynamic information about protein-ion systems, our understanding of the mechanism for specific recognition and protein/ion selectivity remains elusive. Computational and theoretical studies of protein-ion systems using classical models are very challenging due to the lack of accurate and yet computationally tractable classical models for simulating ions in proteins. We propose to systematically investigate the binding of divalent metal ions and phosphate containing ligands to proteins using quantum mechanical calculations and classical molecular dynamics simulations. We will rigorously examine the different types of physical forces in protein-ion interactions using quantum mechanical energy decomposition, and develop a new classical model to accurately describe the physical interactions between ions and protein/water environment. With this new classical model, we will obtain quantitative understanding of the thermodynamic driving forces underlying the specificity and selectivity from molecular dynamics simulations. Given the fundamental importance of protein-ion binding, this research will have a broad impact on advancing our scientific knowledge about ions in biomolecular structure and functions. This research will also lead to computational methods and public software tools that will enable accurate prediction of protein-ion binding and ultimately design of new molecules and proteins targeting specific ions.

Public Health Relevance

The proposed research is important to public health because it will lead to the critical understanding how proteins recognize specific metal and molecular ions for structural and functional purposes, and will provide computational tools that facilitate the discovery of new drugs, protein therapeutics and diagnostic biosensors targeting these ions or ion binding sites in the proteins.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM114237-02
Application #
9062465
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Wehrle, Janna P
Project Start
2015-05-01
Project End
2019-04-30
Budget Start
2016-05-01
Budget End
2017-04-30
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Texas Austin
Department
Biomedical Engineering
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
170230239
City
Austin
State
TX
Country
United States
Zip Code
78712
Laury, Marie L; Wang, Zhi; Gordon, Aaron S et al. (2018) Absolute binding free energies for the SAMPL6 cucurbit[8]uril host-guest challenge via the AMOEBA polarizable force field. J Comput Aided Mol Des 32:1087-1095
Zhang, Changsheng; Lu, Chao; Jing, Zhifeng et al. (2018) AMOEBA Polarizable Atomic Multipole Force Field for Nucleic Acids. J Chem Theory Comput 14:2084-2108
Qi, Rui; Jing, Zhifeng; Liu, Chengwen et al. (2018) Elucidating the Phosphate Binding Mode of Phosphate-Binding Protein: The Critical Effect of Buffer Solution. J Phys Chem B 122:6371-6376
Jing, Zhifeng; Liu, Chengwen; Qi, Rui et al. (2018) Many-body effect determines the selectivity for Ca2+ and Mg2+ in proteins. Proc Natl Acad Sci U S A 115:E7495-E7501
Bell, David R; Cheng, Sara Y; Salazar, Heber et al. (2017) Capturing RNA Folding Free Energy with Coarse-Grained Molecular Dynamics Simulations. Sci Rep 7:45812
Obliosca, Judy M; Cheng, Sara Y; Chen, Yu-An et al. (2017) LNA Thymidine Monomer Enables Differentiation of the Four Single-Nucleotide Variants by Melting Temperature. J Am Chem Soc 139:7110-7116
Liu, Chengwen; Qi, Rui; Wang, Qiantao et al. (2017) Capturing Many-Body Interactions with Classical Dipole Induction Models. J Chem Theory Comput 13:2751-2761
Harger, Matthew; Li, Daniel; Wang, Zhi et al. (2017) Tinker-OpenMM: Absolute and relative alchemical free energies using AMOEBA on GPUs. J Comput Chem 38:2047-2055
Zhang, Changsheng; Bell, David; Harger, Matthew et al. (2017) Polarizable Multipole-Based Force Field for Aromatic Molecules and Nucleobases. J Chem Theory Comput 13:666-678
Deng, Shi; Wang, Qiantao; Ren, Pengyu (2017) Estimating and modeling charge transfer from the SAPT induction energy. J Comput Chem 38:2222-2231

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