Biomolecular simulation for the end-stage refinement of nucleic acid structure: The structure, dynamics, and interactions of nucleic acids are fundamental to their function.
Our aim i s to utilized advanced atomistic simulation methods to perform the "end-stage" refinement of nucleic acid structure with a specific focus on RNA structure, function and drug targeting. To do this, we will refine empirical force fields for representing nucleic acid structure, explore the dynamics (including bendability, twistability and alteration of the properties by the environment of water, salt, proteins and other interacting ligands), and assess the performance on representative model structure. Our integrated set of hypothesis are that: Using improved empirical force fields and improved molecular dynamics and free energy simulation protocols (including enhanced sampling methods), we can (1) perform the "end-stage" refinement and ranking of putative RNA model structures and (2) better understand the interaction of putative drugs with nucleic acids. Moreover, (3) by making datasets and analyses of large sets of MD trajectories of varied nucleic acids generally available, the community will move forward faster in understanding the strengths, limitations, and uses of MD data for representing nucleic acid structure, dynamics, and interaction at multiple scales. It is our aim to refine and rank the relative importance of putative RNA models. In other words, given putative three-dimensional RNA models that satisfy secondary structure restraints, we believe that we can use simulation to move closer to the correct atomic structure and that we can rank the relative importance or reliability of a given model. Applications, beyond a large set of common and representative DNA and RNA structure motifs, include a study of codon-anticodon interactions in the model system of hypermodified tRNAlys interacting with the HIV1-A loop (important for initiation of the virus), optimizing RNA bulged targeting drugs, and detailed characterization of sequence specific structure and dynamics in DNA minicircles and nucleosome positioning sequences. Such studies, beyond providing fundamental insight into nucleic acid structure and dynamics, provide a basis for the development of computer-aided- drug-design strategies for targeting nucleic acid structure (in applications ranging from cancer to antibiotics) and will demonstrate the important role biomolecular simulations can play in deciphering nucleic acid structure / function relationships. Using advanced atomistic simulation methods we will perform the "end-stage" refinement of nucleic acid structure with a specific focus on RNA structure, function and drug targeting and explore a novel data dissemination model where our raw simulation results are made available to the larger community. Such studies, beyond providing fundamental insight into nucleic acid structure and dynamics, provide a basis for the development of computer-aided-drug-design strategies for targeting nucleic acid structure (in applications ranging from cancer to antibiotics) and will demonstrate the important role biomolecular simulations can play in deciphering nucleic acid structure / function relationships.
|Galindo-Murillo, Rodrigo; Roe, Daniel R; Cheatham 3rd, Thomas E (2015) Convergence and reproducibility in molecular dynamics simulations of the DNA duplex d(GCACGAACGAACGAACGC). Biochim Biophys Acta 1850:1041-58|
|Thibault, Julien C; Cheatham 3rd, Thomas E; Facelli, Julio C (2014) iBIOMES Lite: summarizing biomolecular simulation data in limited settings. J Chem Inf Model 54:1810-9|
|Pasi, Marco; Maddocks, John H; Beveridge, David et al. (2014) ?ABC: a systematic microsecond molecular dynamics study of tetranucleotide sequence effects in B-DNA. Nucleic Acids Res 42:12272-83|
|Roe, Daniel R; Bergonzo, Christina; Cheatham 3rd, Thomas E (2014) Evaluation of enhanced sampling provided by accelerated molecular dynamics with Hamiltonian replica exchange methods. J Phys Chem B 118:3543-52|
|Galindo-Murillo, Rodrigo; Roe, Daniel R; Cheatham 3rd, Thomas E (2014) On the absence of intrahelical DNA dynamics on the ?s to ms timescale. Nat Commun 5:5152|
|Henriksen, Niel M; Hayatshahi, Hamed S; Davis, Darrell R et al. (2014) Structural and energetic analysis of 2-aminobenzimidazole inhibitors in complex with the hepatitis C virus IRES RNA using molecular dynamics simulations. J Chem Inf Model 54:1758-72|
|Sponer, Jiri; Mladek, Arnost; Spackova, Naýýa et al. (2013) Relative stability of different DNA guanine quadruplex stem topologies derived using large-scale quantum-chemical computations. J Am Chem Soc 135:9785-96|
|Cheatham 3rd, Thomas E; Case, David A (2013) Twenty-five years of nucleic acid simulations. Biopolymers 99:969-77|
|Thibault, Julien C; Facelli, Julio C; Cheatham 3rd, Thomas E (2013) iBIOMES: managing and sharing biomolecular simulation data in a distributed environment. J Chem Inf Model 53:726-36|
|Zgarbova, Marie; Luque, F Javier; Sponer, Jiri et al. (2013) Toward Improved Description of DNA Backbone: Revisiting Epsilon and Zeta Torsion Force Field Parameters. J Chem Theory Comput 9:2339-2354|
Showing the most recent 10 out of 18 publications