Molecular dynamics (MD) simulations is a powerful computational tool in structural biology, widely used for understanding conformational changes in proteins, and folding of peptides. However MD simulations using Cartesian dynamics model is limited by the total simulation time scale being in tens of nanoseconds for large proteins. Biological processes on the other hand need microseconds of simulation time. Internal Coordinate Molecular Dynamics (ICMD) algorithms have been developed to enable larger simulation time-steps and they show great promise in long time scale simulations. Despite their promise, ICMD techniques have made little progress due in large part to the additional mathematical complexity of internal coordinate models. We propose to address and solve the key bottleneck problems with ICMD algorithms. We propose to develop, validate Generalized NEIMO (GNEIMO) ICMD methods that allow freezing of only bond lengths, bond angle and bond lengths and use of ICMD methods for wider conformational search using model coarsening strategies. We also propose to characterize the performance of ICMD algorithms for the applications such as 1) maintaining the native protein structure, 2) refinement of a near native homology structural models, 3) folding of alpha helical and beta hairpin peptides and 4) conformations changes in small proteins. Together, the various studies within this project will provide algorithms and a roadmap for the effective use of ICMD. We will lay the basis for integration of these algorithms with the widely used MD software package NAMD for wider dissemination.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-MSFD-N (01))
Program Officer
Brazhnik, Paul
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
City of Hope/Beckman Research Institute
United States
Zip Code
Choy, Cecilia; Ansari, Khairul I; Neman, Josh et al. (2017) Cooperation of neurotrophin receptor TrkB and Her2 in breast cancer cells facilitates brain metastases. Breast Cancer Res 19:51
Kandel, Saugat; Salomon-Ferrer, Romelia; Larsen, Adrien B et al. (2016) Overcoming potential energy distortions in constrained internal coordinate molecular dynamics simulations. J Chem Phys 144:044112
Vaidehi, Nagarajan; Jain, Abhinandan (2015) Internal coordinate molecular dynamics: a foundation for multiscale dynamics. J Phys Chem B 119:1233-42
Larsen, Adrien B; Wagner, Jeffrey R; Jain, Abhinandan et al. (2014) Protein structure refinement of CASP target proteins using GNEIMO torsional dynamics method. J Chem Inf Model 54:508-17
Neman, Josh; Termini, John; Wilczynski, Sharon et al. (2014) Human breast cancer metastases to the brain display GABAergic properties in the neural niche. Proc Natl Acad Sci U S A 111:984-9
Larsen, Adrien B; Wagner, Jeffrey R; Kandel, Saugat et al. (2014) GneimoSim: a modular internal coordinates molecular dynamics simulation package. J Comput Chem 35:2245-55
Jain, Abhinandan; Kandel, Saugat; Wagner, Jeffrey et al. (2013) Fixman compensating potential for general branched molecules. J Chem Phys 139:244103
Gangupomu, Vamshi K; Wagner, Jeffrey R; Park, In-Hee et al. (2013) Mapping conformational dynamics of proteins using torsional dynamics simulations. Biophys J 104:1999-2008
Wagner, Jeffrey R; Balaraman, Gouthaman S; Niesen, Michiel J M et al. (2013) Advanced techniques for constrained internal coordinate molecular dynamics. J Comput Chem 34:904-14
Jain, Abhinandan; Park, In-Hee; Vaidehi, Nagarajan (2012) Equipartition Principle for Internal Coordinate Molecular Dynamics. J Chem Theory Comput 8:2581-2587

Showing the most recent 10 out of 16 publications