Due the limitations of both simulation and experiment, an ultimate understanding of protein folding will come from a coupled approach of detailed simulations extensively validated and tested by experiment. However, developing simulation methodology which can quantitatively connect with experimental kinetics still remains a great theoretical challenge, due to the long timescales involved and the difficulties and complexities of detailed, atomistic models. Here, we propose new, third generation distributed computing methods to tackle these challenges and the application of these methods to questions related to how proteins self-assemble in solution as well as in the biologically relevant contexts. While protein folding has itself been studied computationally for many years, our work differs from other approaches in (1) its use of innovative distributed computing methods for simulating long, biologically relevant time scale kinetics (on the millisecond to second timescale - dramatically longer than the previous state of the art) and for large and complex proteins (on the 100+ amino acid length scale) using detailed, fully atomistic, explicit solvent models and (2) the application of these detailed models to address questions of folding in the biological contexts of different environments in the cell. Moreover, we are able to perform a quantitative comparison to experiment, which is critical for both the testing and greater impact of our computational methods; indeed, key experimental collaborations using cutting edge methods are proposed to make direct connections to our proposed simulations. Finally, the proposed work would have an impact on our basic understanding of several protein-related diseases, such protein misfolding diseases, such as Alzheimer's Disease and Huntington's Disease. Indeed, methodology from the previous project period has already lead to advances in the simulation of peptide aggregation in Alzheimer's and Huntington's Disease. Also, by understanding the nature of folding in biological contexts, such as in the presence of membranes, in biologically confined spaces, and with crowding agents, and by directly comparing those simulations to novel experiments of folding in the cell, we would gain insight into the nature of protein folding in viv, which is the next important step in our understanding of protein folding and its connection to biology and biomedical questions.
The study of protein folding is going through a renaissance: with the ability to now simulate the folding of significantly sized proteins on the millisecond timescale (and soon up to the seconds timescale), theory can tackle interesting and important problems. Due to its connection with protein misfolding disease and recent experimental and theoretical indications of misfolded protein intermediate states, we propose to examine the role of non-native interactions, especially by making connections to key experimental results in this area.
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| Sinitskiy, Anton V; Pande, Vijay S (2018) Computer Simulations Predict High Structural Heterogeneity of Functional State of NMDA Receptors. Biophys J 115:841-852 |
| Wagoner, Jason A; Pande, Vijay S (2018) Communication: Adaptive boundaries in multiscale simulations. J Chem Phys 148:141104 |
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| McKiernan, Keri A; Husic, Brooke E; Pande, Vijay S (2017) Modeling the mechanism of CLN025 beta-hairpin formation. J Chem Phys 147:104107 |
| McGibbon, Robert T; Husic, Brooke E; Pande, Vijay S (2017) Identification of simple reaction coordinates from complex dynamics. J Chem Phys 146:044109 |
| Sinitskiy, Anton V; Stanley, Nathaniel H; Hackos, David H et al. (2017) Computationally Discovered Potentiating Role of Glycans on NMDA Receptors. Sci Rep 7:44578 |
| Harrigan, Matthew P; McKiernan, Keri A; Shanmugasundaram, Veerabahu et al. (2017) Markov modeling reveals novel intracellular modulation of the human TREK-2 selectivity filter. Sci Rep 7:632 |
| Husic, Brooke E; Pande, Vijay S (2017) Note: MSM lag time cannot be used for variational model selection. J Chem Phys 147:176101 |
| Lopez, Tom; Dalton, Kevin; Tomlinson, Anthony et al. (2017) An information theoretic framework reveals a tunable allosteric network in group II chaperonins. Nat Struct Mol Biol 24:726-733 |
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