Ensembles of molecular dynamics engines for assessing force fields, conformational change, and free energies of proteins and nucleic acids

Thomas Cheatham, University of Utah

Usage Details

Thomas Cheatham, Andre Merzky, Adrian Roitberg, Daniel Roe, Victor Anisimov, Christina Bergonzo, Mark Santcroos, Kevin Hauser, Rodrigo Galindo, Chad Hopkins, Sean Cornillie, James Robertson, Natali Di Russo, Pancham Lal Gupta, Kenneth Lam, Jinfeng Liu, Jordi Juarez-Jimenez, He Huang, Koushik Kasavajhala, Justin Smith, Ankita Sarkar, Dylan MacPhee, Antons Treikalis, Travis Hughes, Kellon Belfon, Chuan Tian, Vivekanandan Balasubramanian, Angela Migues, Timothy Giese, Haoyuan Chen, Ming Huang, Colin Gaines, Ken Kostenbader, Junjie Ouyang, Sunidhi Lenka, Maria del Pilar Buteler, Stephanie Portillo, Blair Weaver, Carlos Modenutti, Vinicius Wilian Cruzeiro, Dominic Rufa, Delaram Ghoreishi, Natalia Rojas, Christian Devereux, Zachary Fallon, Jennifer Madrigal, Patricio Barletta, Pablo Palestro, Rodrigo Tosso

Using Blue Waters, our research centers on developing and applying accurate methods for the simulation of biomolecules using the AMBER software. Using ensembles of these simulations, we can efficiently model the conformational distributions of biomolecules to better understand their structure, dynamics and interactions, and ultimately this provides detailed information about their function. This information can be used to design drugs to modulate function and to help determine how to alter the biomolecular structure and dynamics to influence function. Over the past few years, using these technologies we have shown the ability to reproducibly converge the conformational distributions (i.e. the set of conformations sampled under a particular set of conditions, such as at a particular temperature, pH, or specific environment) of various RNA molecules. We have also improved the molecular "force fields" that allow proper modeling of the structure and dynamics. This generally allows us to better understand how biomolecular machines, including various protein and RNA molecules, function. For example, one of our goals is to understand how riboswitches recognize specific metabolites which in turn leads to conformational changes that alters regulation of those metabolites. Another goal is to better understand the structure and dynamics of biomolecules in the crystal and this will lead to a better understanding of the role of structure and disorder in protein function. The methods and "force fields" developed are in wide use by a larger community that is aiming to provide realistic insight into biomolecular structure, dynamics, and function. Although not all research groups have access to the Blue Waters petascale resource at this time, the technology we are developing and applying now will become routinely accessible to the larger community who can then easily apply these methods on future resources. Since computer power and accessibility continues to grow at a rapid pace, the broader community will see the impact of these technologies within a few years.

Advances in simulation methods and increases in computational power have coupled together over the past few decades to transform our understanding of biological macromolecules; we can watch small proteins fold to their correct structure, we can help design new therapeutics, and improved simulation methods can help refine low resolution or ambiguous experimental data. The biomolecular simulation methods we apply add to experimental data by exposing information not readily measured about the motions of biomolecules across many size and time scales, ranging from the fastest bond vibrations to slower collective motions. This allows elucidation of the dynamic landscape of proteins and nucleic acids as a function of time, especially at smaller scales. Access to petascale computational resources allows us for the first time to fully explore the structural, dynamic and energetic landscape of complex biomolecules. In our current PRAC, we have been able to fully converge the conformational ensemble of DNA helices, RNA tetranucleotides and tetraloops, we assessed and improved the force fields, and we also developed novel multi-dimensional replica-exchange methods and analysis tools. With further collaboration of an experienced team of AMBER developers, we aim to decipher the full landscape of protein and nucleic acid structure and function, with a heavy focus on RNA, DNA and proteins and their complexes. On Blue Waters we will continue to hierarchically and tightly couple ensembles of highly GPU optimized molecular dynamics engines to fully map out the conformational, energetic and chemical landscape of biomolecules. This will be done not only to assess, validate and improve currently available biomolecular force fields, but also to provide novel insight into DNA structure in the crystal and in solution, RNA riboswitch dynamics and function, and also protein-nucleic acid interactions. Additional aims focus on the development of new analysis methods and dissemination of the simulation data to the larger community for deeper and broader inspection.