The TINKER Molecular Modeling package is a modular, extensible set of computational biology programs intended to serve as a test-bed for empirical potentials (""""""""force fields"""""""") and algorithm development. TINKER is freely available in both executable and source code form, and has seen extensive use in both academic and industrial labs worldwide. An important capability of the package is its ability to perform energy calculations with a number of alternative present-generation force field parameter sets. The current project intends to extend this comparative capability to emerging polarizable energy models for biomolecular simulation. Further development of the Force Field Explorer graphical interface to TINKER will enable visualization of electrostatic effects, such as polarization, and remote monitoring of TINKER calculations. Distributed memory parallelization, advanced Ewald summation methods, and other code optimizations will allow efficient use of TINKER on commodity Beowulf clusters and similar computer hardware. Force fields are the cornerstone of a vast array of atomic-level biomolecular modeling techniques derived from classical principles of chemical physics. As such, """"""""molecular mechanics"""""""" software sees use in a variety of research and educational settings. A primary goal of this project is to produce a """"""""next-generation"""""""" energy model that will routinely provide """"""""chemical accuracy"""""""" of 0.5 kcal/mol or better for the thermodynamics of ligand binding and for intramolecular biopolymer interactions. Structure-based drug design and highresolution homology modeling, in particular, will benefit from the resulting accuracy improvements. The AMOEBA polarizable atomic multipole model, which provides a flexible and accurate description of the underlying permanent electrostatics and response to the molecular environment, will be extended to nucleic acids. The ready availability of documented source code and parameters will enable the incorporation of the new polarizable potential into other widely-used modeling suites. Applications will focus on calculation of absolute binding constants in systems of biological importance, protein loop modeling, side chain rotamer prediction and structure refinement. The structure and energetics of ion-containing systems will also be investigated, since polarization is widely considered to play a key role in problems such as ion transport through membrane protein channels, ion mobility and concentration in DNA grooves.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BST-D (51))
Program Officer
Whitmarsh, John
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Schools of Medicine
Saint Louis
United States
Zip Code
Kuster, Daniel J; Liu, Chengyu; Fang, Zheng et al. (2015) High-resolution crystal structures of protein helices reconciled with three-centered hydrogen bonds and multipole electrostatics. PLoS One 10:e0123146
Liu, Chengyu; Ponder, Jay W; Marshall, Garland R (2014) Helix stability of oligoglycine, oligoalanine, and oligo-?-alanine dodecamers reflected by hydrogen-bond persistence. Proteins 82:3043-61
Xiang, Jin Yu; Ponder, Jay W (2013) A valence bond model for aqueous Cu(II) and Zn(II) ions in the AMOEBA polarizable force field. J Comput Chem 34:739-49
Zheng, Xiange; Wu, Chuanjie; Ponder, Jay W et al. (2012) Molecular dynamics of ?-hairpin models of epigenetic recognition motifs. J Am Chem Soc 134:15970-8
Ren, Pengyu; Wu, Chuanjie; Ponder, Jay W (2011) Polarizable Atomic Multipole-based Molecular Mechanics for Organic Molecules. J Chem Theory Comput 7:3143-3161
Ponder, Jay W; Wu, Chuanjie; Ren, Pengyu et al. (2010) Current status of the AMOEBA polarizable force field. J Phys Chem B 114:2549-64
Schnieders, Michael J; Baker, Nathan A; Ren, Pengyu et al. (2007) Polarizable atomic multipole solutes in a Poisson-Boltzmann continuum. J Chem Phys 126:124114