Chen AA, Marucho M, Baker NA, Pappu RV. Simulations of RNA interactions with monovalent ions. Methods in Enzymology, 469, 411-432, 2009.
RNA folding and binding reactions are mediated by interactions with ions that make up the surrounding aqueous electrolytic milieu. Although Mg2+ ions are often implicated as being crucial for RNA folding, it is known that folding is feasible in high concentrations of monovalent alkali-halide salts. Experiments have yielded important information regarding the salt dependence of RNA stability. Recent work has shown that molecular simulations based on explicit representations of solvent molecules and monovalent ions can also provide useful insights regarding the ionic atmospheres around model RNA systems. These insights can help rationalize intriguing observations regarding the dependence of RNA stability on cation type providing one pays attention to important considerations that go into the proper design of molecular simulations. These issues are discussed in detail and the methods are applied to an A-form RNA and B-form DNA sequence. The results of these simulations are compared to previous work on a kissing-loop system with analogous sequence. In particular, ionic atmospheres obtained from molecular simulations are compared to those obtained using the nonlinear Poisson Boltzmann model for continuum electrostatics for these three different nucleic acid systems. The comparisons indicate reasonable agreement in terms of coarse-grained observables such as the numbers of counterions accumulated around the solutes. However, details of the ionic atmospheres, captured in terms of spatial free energy density profiles, are quite different between the two approaches. These comparisons suggest the need for improvements in continuum models to capture sequence-specific effects, ion–ion correlation, and the effects of partial dehydration of ions.
Zhang D, Konecny R, Baker NA, McCammon JA. Electrostatic interaction between RNA and protein capsid in CCMV simulated by a coarse-grain RNA model and a Monte Carlo approach. Biopolymers, 75, 325-337, 2004.
Although many viruses have been crystallized and the protein capsid structures have been determined by x-ray crystallography, the nucleic acids often cannot be resolved. This is especially true for RNA viruses. The lack of information about the conformation of DNA/RNA greatly hinders our understanding of the assembly mechanism of various viruses. Here we combine a coarse-grain model and a Monte Carlo method to simulate the distribution of viral RNA inside the capsid of cowpea chlorotic mottle virus. Our results show that there is very strong interaction between the N-terminal residues of the capsid proteins, which are highly positive charged, and the viral RNA. Without these residues, the binding energy disfavors the binding of RNA by the capsid. The RNA forms a shell close to the capsid with the highest densities associated with the capsid dimers. These high-density regions are connected to each other in the shape of a continuous net of triangles. The overall icosahedral shape of the net overlaps with the capsid subunit icosahedral organization. Medium density of RNA is found under the pentamers of the capsid. These findings are consistent with experimental observations.
Vitalis A, Baker NA, McCammon JA. ISIM: a program for grand canonical Monte Carlo simulations of the ionic environment of biomolecules. Mol Sim, 30, 45-61, 2004.
In this work we present a new software package (ISIM), which represents a flexible, computational tool for simulations of electrolyte solutions via a grand canonical Monte Carlo procedure (GCMC) with a specific capability of treating biomolecules in solution. The GCMC method provides a powerful tool for studying the ionic environments of highly charged macromolecules with attention to the atomic detail of both the solute and the mobile counterions. The ISIM software differs from previous schemes mainly by treating different ion types independently and offering a new parameterization procedure for calibrating excess chemical potentials and bulk ion concentrations. Additionally, ISIM leverages the APBS software package to provide accurate descriptions of the biomolecular electrostatic potential through the efficient solution of Poisson’s equation. ISIM has been validated on a variety of test systems; we successfully reproduce elementary properties of electrolyte solutions as well as theoretical and experimental results for challenging test systems like Calmodulin and DNA.
DOI: 10.1080/08927020310001597862
Malany S, Baker N, Verweyst M, Medhekar R, Quinn DM, Velan B, Kronman C, Shafferman A. Theoretical and experimental investigations of electrostatic effects on acetylcholinesterase catalysis and inhibition. Chem-Biol Interact, 120, 99-110, 1999.
The role of electrostatics in the function of acetylcholinesterase (AChE) has been investigated by both theoretical and experimental approaches. Second-order rate constants (kE = k(cat)/Km) for acetylthiocholine (ATCh) turnover have been measured as a function of ionic strength of the reaction medium for wild-type and mutant AChEs. Also, binding and dissociation rate constants have been measured as a function of ionic strength for the respective charged and neutral transition state analog inhibitors m-(N,N,N-trimethylammonio)trifluoroacetophenone (TMTFA) and m-(t-butyl)trifluoroacetophenone (TBTFA). Linear free-energy correlations between catalytic rate constants and inhibition constants indicate that kE for ATCh turnover is rate limited by terminal binding events. Comparison of binding rate constants for TMTFA and TBTFA attests to the sizable electrostatic discrimination of AChE. Free energy profiles for cationic ligand release from the active sites of wild-type and mutant AChEs have been calculated via a model that utilizes the structure of T. californica AChE, a spherical ligand, and energy terms that account for electrostatic and van der Waals interactions and chemical potential. These calculations indicate that EA and EI complexes are not bound with respect to electrostatic interactions, which obviates the need for a ‘back door’ for cationic ligand release. Moreover, the computed energy barriers for ligand release give linear free-energy correlations with log(kE) for substrate turnover, which supports the general correctness of the computational model.
RNA folding and binding reactions are mediated by interactions with ions that make up the surrounding aqueous electrolytic milieu. Although Mg2+ ions are often implicated as being crucial for RNA folding, it is known that folding is feasible in high concentrations of monovalent alkali-halide salts. Experiments have yielded important information regarding the salt dependence of RNA stability. Recent work has shown that molecular simulations based on explicit representations of solvent molecules and monovalent ions can also provide useful insights regarding the ionic atmospheres around model RNA systems. These insights can help rationalize intriguing observations regarding the dependence of RNA stability on cation type providing one pays attention to important considerations that go into the proper design of molecular simulations. These issues are discussed in detail and the methods are applied to an A-form RNA and B-form DNA sequence. The results of these simulations are compared to previous work on a kissing-loop system with analogous sequence. In particular, ionic atmospheres obtained from molecular simulations are compared to those obtained using the nonlinear Poisson Boltzmann model for continuum electrostatics for these three different nucleic acid systems. The comparisons indicate reasonable agreement in terms of coarse-grained observables such as the numbers of counterions accumulated around the solutes. However, details of the ionic atmospheres, captured in terms of spatial free energy density profiles, are quite different between the two approaches. These comparisons suggest the need for improvements in continuum models to capture sequence-specific effects, ion–ion correlation, and the effects of partial dehydration of ions.
