The goals of the proposed research are to (1) to derive a set of suitable atomic radii for use in continuum dielectric Poisson-Boltzmann (PB) and solvent accessibility (SA) implicit solvent calculations within the context of a Drude polarizable force field and (2) apply this extended PB-polarizable force field treatment to RNA molecules of increasing complexity to quantify the driving forces for RNA folding, stability, and dynamics. The overarching objective is to study RNA folding by quantifying the free energy differences between conformational states and thus describe folding pathways for RNA in a quantitative manner. The PB/SA methodology could also be used in protein simulations. Simulations of RNA folding will be conducted using enhanced sampling methods to investigate folded, unfolded, and intermediate states of RNA molecules with various features (hairpins, pseudoknots, etc). Free energies from the MM/PBSA calculations will be coupled with information on base stacking energetics from quantum mechanics (QM) calculations to obtain a quantitative molecular understanding of events occurring during RNA folding. This information is important not only from a fundamental standpoint of understanding RNA folding, but also due to the fact that mutations in RNA that cause misfolding often lead to disease. In addition, studies on the SAM-II riboswitch, which binds S-adenosylmethionine (SAM) in bacteria, will be used to quantitatively describe the differences in apo- and SAM-bound configurations. Since many bacterial species use riboswitches to control gene expression, the proposed studies will provide information that can be used in the development of novel antibiotics. Polarizable force fields are especially relevant in these studies since the conformations of the strongly charged RNA molecules are highly dynamic and dependent upon metal binding. The three Aims described in this project are: 1. Extend the existing Drude polarizable force field to include parameters for MM/PBSA calculations. The use of MM/PBSA calculations allows for accurate estimates of free energies of macromolecular configurations. Atomic radii for MM/PBSA calculations will be tuned based on free energies of solvation from FEP and experiments. 2. Quantitate the effect of polarization on the folding and stabilization of small RNA molecules. RNA folding pathways are complex, and driving forces are not completely understood. Using enhanced sampling methods in conjunction with MM/PBSA and QM calculations, we will quantitate the role of polarization and metal binding on the folding pathway(s) of small RNA molecules. 3. Investigate the dynamics and free energy between conformational states of the SAM-II riboswitch. Riboswitch function depends on conformational changes induced by metabolite binding. In this Aim, we will investigate the driving forces behind these binding events and the resulting conformational changes.

Public Health Relevance

Misfolding of RNA molecules gives rise to several diseases such as cystic fibrosis, parkinsonism, and cancer. Understanding the underlying molecular basis of RNA misfolding will aid in understanding the origins of these diseases. Further, new insights into riboswitch dynamics and their interactions with metabolites will lead to important insights that are to be used in the development of new antibiotics.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F04-W (20))
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Flicker, Paula F
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University of Maryland Baltimore
Schools of Pharmacy
United States
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Lemkul, Justin A; MacKerell Jr, Alexander D (2018) Polarizable force field for RNA based on the classical drude oscillator. J Comput Chem 39:2624-2646
Huang, Jing; Lemkul, Justin A; Eastman, Peter K et al. (2018) Molecular dynamics simulations using the drude polarizable force field on GPUs with OpenMM: Implementation, validation, and benchmarks. J Comput Chem 39:1682-1689
Lemkul, Justin A; MacKerell Jr, Alexander D (2017) Polarizable Force Field for DNA Based on the Classical Drude Oscillator: I. Refinement Using Quantum Mechanical Base Stacking and Conformational Energetics. J Chem Theory Comput 13:2053-2071
Klontz, Erik H; Tomich, Adam D; Günther, Sebastian et al. (2017) Structure and Dynamics of FosA-Mediated Fosfomycin Resistance in Klebsiella pneumoniae and Escherichia coli. Antimicrob Agents Chemother 61:
Lemkul, Justin A; MacKerell Jr, Alexander D (2017) Polarizable Force Field for DNA Based on the Classical Drude Oscillator: II. Microsecond Molecular Dynamics Simulations of Duplex DNA. J Chem Theory Comput 13:2072-2085
Lemkul, Justin A; Lakkaraju, Sirish Kaushik; MacKerell Jr, Alexander D (2016) Characterization of Mg2+ Distributions around RNA in Solution. ACS Omega 1:680-688
Lee, Jumin; Cheng, Xi; Swails, Jason M et al. (2016) CHARMM-GUI Input Generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM/OpenMM Simulations Using the CHARMM36 Additive Force Field. J Chem Theory Comput 12:405-13
Soteras Gutiérrez, Ignacio; Lin, Fang-Yu; Vanommeslaeghe, Kenno et al. (2016) Parametrization of halogen bonds in the CHARMM general force field: Improved treatment of ligand-protein interactions. Bioorg Med Chem 24:4812-4825
Lakkaraju, Sirish Kaushik; Lemkul, Justin A; Huang, Jing et al. (2016) DIRECT-ID: An automated method to identify and quantify conformational variations--application to ?2 -adrenergic GPCR. J Comput Chem 37:416-25
Lemkul, Justin A; MacKerell Jr, Alexander D (2016) Balancing the Interactions of Mg2+ in Aqueous Solution and with Nucleic Acid Moieties For a Polarizable Force Field Based on the Classical Drude Oscillator Model. J Phys Chem B 120:11436-11448

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