The aromatic stacking of saturated hydrocarbons in aqueous solution has been commonly interpreted by the hydrophobic effect that dissolution is opposed by water's preference for interacting with itself relative to interacting with the hydrocarbon, and that water molecules forced to reside near the nonpolar solute have excess energy that is manifested in a higher degree of order than that of bulk water. In contrast, the self-association of heterocycles in aqueous solution has been interpreted to imply that these associations are driven by intrinsic attractions between the heterocyclic rings, namely, the dispersion force and interactions between partial charges on the heterocyclic rings, and a """"""""hidden"""""""" hydrophobic effect. Recently, Gellman et al. have suggested that the aromatic stacking between two heterocyclic moieties, or between a hydrocarbon and a heterocycle, is not a result of the hydrophobic effect, and that the dispersion force is not a dominant promoter of aromatic stacking, based on their NMR study on bis-adenine, bis-phenyl, and bis-naphthyl compounds with a propylene linker. To investigate the aromatic stacking in further detail, we are using molecular dynamics (MD) simulations and potential of mean force (PMF) calculations on the compounds used in Gellman's NMR experiment are proposed, with the aid of the AMBER 4.1 and MidasPlus programs in the Computer Graphics Lab, in hope that molecular dynamics simulations will provide distinctive, dynamic profiles for the stacking behaviors of bis-adenine and bis-naphthyl compounds and insights into understanding the nature of aromatic stacking interaction, and that PMF calculation will provide more conclusive information on the stability of the stacking and non-stacking conformers. In addition, MD simulations and PMF calculations on other compounds (e.g., bis-indole, bis-benzothiophene, and bis-benzofuran analogs) are proposed in an attempt to investigate if the different behaviors of the aromatic stacking of bis-naphthyl and bis-adenine compounds observed in the NMR study stem from the different molecular volumes (6 membered ring versus 5 membered ring) or the different connecting points (meta position versus ortho position) of the naphthyl and adenine groups. Preliminary MD simulations and PMF calculations on bis-n-methylindole acetic acid revealed that the non-stacking conformer is more stable than the stacking conformer in aqueous solution, which is consistent with Gellman's suggestion that the aromatic stacking between two heterocyclic moieties or between a hydrocarbon and a heterocycle stems only from electrostatic interaction.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Biotechnology Resource Grants (P41)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Francisco
San Francisco
United States
Zip Code
Kozak, John J; Gray, Harry B; Garza-López, Roberto A (2018) Relaxation of structural constraints during Amicyanin unfolding. J Inorg Biochem 179:135-145
Alamo, Lorenzo; Pinto, Antonio; Sulbarán, Guidenn et al. (2018) Lessons from a tarantula: new insights into myosin interacting-heads motif evolution and its implications on disease. Biophys Rev 10:1465-1477
Viswanath, Shruthi; Chemmama, Ilan E; Cimermancic, Peter et al. (2017) Assessing Exhaustiveness of Stochastic Sampling for Integrative Modeling of Macromolecular Structures. Biophys J 113:2344-2353
Chu, Shidong; Zhou, Guangyan; Gochin, Miriam (2017) Evaluation of ligand-based NMR screening methods to characterize small molecule binding to HIV-1 glycoprotein-41. Org Biomol Chem 15:5210-5219
Portioli, Corinne; Bovi, Michele; Benati, Donatella et al. (2017) Novel functionalization strategies of polymeric nanoparticles as carriers for brain medications. J Biomed Mater Res A 105:847-858
Alamo, Lorenzo; Koubassova, Natalia; Pinto, Antonio et al. (2017) Lessons from a tarantula: new insights into muscle thick filament and myosin interacting-heads motif structure and function. Biophys Rev 9:461-480
Nguyen, Hai Dang; Yadav, Tribhuwan; Giri, Sumanprava et al. (2017) Functions of Replication Protein A as a Sensor of R Loops and a Regulator of RNaseH1. Mol Cell 65:832-847.e4
Sofiyev, Vladimir; Kaur, Hardeep; Snyder, Beth A et al. (2017) Enhanced potency of bivalent small molecule gp41 inhibitors. Bioorg Med Chem 25:408-420
Nekouzadeh, Ali; Rudy, Yoram (2016) Conformational changes of an ion-channel during gating and emerging electrophysiologic properties: Application of a computational approach to cardiac Kv7.1. Prog Biophys Mol Biol 120:18-27
Towse, Clare-Louise; Vymetal, Jiri; Vondrasek, Jiri et al. (2016) Insights into Unfolded Proteins from the Intrinsic ?/? Propensities of the AAXAA Host-Guest Series. Biophys J 110:348-361

Showing the most recent 10 out of 508 publications