Towards Computational Modeling of Ligand Binding to the ILPR G-Quadruplex

Using a combination of unconstrained and constrained molecular dynamics simulations, we have evaluated the binding affinities between two porphyrin derivatives (TMPyP4 and TEGPy) and the G-quadruplex (G4) of a DNA fragment modeling the insulin-linked polymorphic region (ILPR). Refining a well-established potential of mean force (PMF) approach to selections of constraints based on root-mean-square fluctuations results in an excellent agreement between the calculated and observed absolute free binding energy of TMPyP4. The binding affinity of IPLR-G4 toward TEGPy is predicted to be higher than that toward TMPyP4 by 2.5 kcal/mol, which can be traced back to stabilization provided by the polyether side chains of TMPyP4 that can nestle into the grooves of the quadruplex and form hydrogen bonds through the ether oxygen atoms. Because our refined methodology can be applied to large ligands with high flexibility, the present research opens an avenue for further ligand design in this important area.

[1]  Sobhan Sen,et al.  G-Tetrad-Selective Ligand Binding Kinetics in G-Quadruplex DNA Probed with Fluorescence Correlation Spectroscopy. , 2022, The journal of physical chemistry. B.

[2]  S. Balasubramanian,et al.  G-quadruplexes are transcription factor binding hubs in human chromatin , 2021, Genome biology.

[3]  Young Jun Seo,et al.  Loop-mediated fluorescent probes for selective discrimination of parallel and antiparallel G-Quadruplexes. , 2021, Bioorganic & medicinal chemistry.

[4]  A. Mulholland,et al.  Enhanced sampling molecular dynamics simulations correctly predict the diverse activities of a series of stiff-stilbene G-quadruplex DNA ligands , 2020, Chemical science.

[5]  Wenjie Mei,et al.  Selective stabilization of multiple promoter G-quadruplex DNA by using 2-phenyl-1H-imidazole-based tanshinone IIA derivatives and their potential suppressing function in the metastatic breast cancer. , 2020, Bioorganic chemistry.

[6]  S. Balasubramanian,et al.  The regulation and functions of DNA and RNA G-quadruplexes , 2020, Nature Reviews Molecular Cell Biology.

[7]  S. Balasubramanian,et al.  The regulation and functions of DNA and RNA G-quadruplexes , 2020, Nature Reviews Molecular Cell Biology.

[8]  C. Bannwarth,et al.  GFN2-xTB-An Accurate and Broadly Parametrized Self-Consistent Tight-Binding Quantum Chemical Method with Multipole Electrostatics and Density-Dependent Dispersion Contributions. , 2018, Journal of chemical theory and computation.

[9]  Xiang Zhou,et al.  G-Quadruplex: A Regulator of Gene Expression and Its Chemical Targeting , 2018, Chem.

[10]  Xiaodong Ye,et al.  Sedimentation velocity analysis of TMPyP4-induced dimer formation of human telomeric G-quadruplex , 2017 .

[11]  P. Cieplak,et al.  Resolving the Ligand-Binding Specificity in c-MYC G-Quadruplex DNA: Absolute Binding Free Energy Calculations and SPR Experiment. , 2017, The journal of physical chemistry. B.

[12]  X. Xi,et al.  Involvement of G-triplex and G-hairpin in the multi-pathway folding of human telomeric G-quadruplex , 2017, Nucleic acids research.

[13]  Stephen Neidle,et al.  Quadruplex nucleic acids as targets for anticancer therapeutics , 2017 .

[14]  B. Fedeles.  G-quadruplex–forming promoter sequences enable transcriptional activation in response to oxidative stress , 2017, Proceedings of the National Academy of Sciences.

[15]  Stefano Alcaro,et al.  Ligand binding to telomeric G-quadruplex DNA investigated by funnel-metadynamics simulations , 2017, Proceedings of the National Academy of Sciences.

[16]  Yuanlong Ge,et al.  Conformation Selective Antibody Enables Genome Profiling and Leads to Discovery of Parallel G-Quadruplex in Human Telomeres. , 2016, Cell chemical biology.

[17]  J. Boudon,et al.  DNA structure-specific sensitization of a metalloporphyrin leads to an efficient in vitro quadruplex detection molecular tool , 2016 .

[18]  James C. Robertson,et al.  Assessing the Current State of Amber Force Field Modifications for DNA , 2016, Journal of chemical theory and computation.

[19]  D. Case,et al.  PARMBSC1: A REFINED FORCE-FIELD FOR DNA SIMULATIONS , 2015, Nature Methods.

[20]  A. Moye,et al.  Telomeric G-quadruplexes are a substrate and site of localization for human telomerase , 2015, Nature Communications.

[21]  E. Lesniewska,et al.  Surface-promoted aggregation of amphiphilic quadruplex ligands drives their selectivity for alternative DNA structures. , 2015, Organic & biomolecular chemistry.

[22]  M. Bansal,et al.  Ligand 5,10,15,20-tetra(N-methyl-4-pyridyl)porphine (TMPyP4) prefers the parallel propeller-type human telomeric G-quadruplex DNA over its other polymorphs. , 2015, The journal of physical chemistry. B.

[23]  D. Melton,et al.  Generation of Functional Human Pancreatic β Cells In Vitro , 2014, Cell.

[24]  James D. Johnson,et al.  Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells , 2014, Nature Biotechnology.

[25]  Deming Kong,et al.  Two cationic porphyrin isomers showing different multimeric G-quadruplex recognition specificity against monomeric G-quadruplexes , 2014, Nucleic acids research.

[26]  Katrin Paeschke,et al.  DNA secondary structures: stability and function of G-quadruplex structures , 2012, Nature Reviews Genetics.

[27]  Berk Hess,et al.  Driving forces for adsorption of amphiphilic peptides to the air-water interface. , 2010, The journal of physical chemistry. B.

[28]  S. Firestine,et al.  Characterization of Insulin Ilpr Sequences for Their Ability to Adopt a G-Quadruplex Structure , 2010, Nucleosides, nucleotides & nucleic acids.

[29]  B. Pagano,et al.  Shedding light on the interaction between TMPyP4 and human telomeric quadruplexes. , 2009, The journal of physical chemistry. B.

[30]  L. Hurley,et al.  The importance of negative superhelicity in inducing the formation of G-quadruplex and i-motif structures in the c-Myc promoter: implications for drug targeting and control of gene expression. , 2009, Journal of medicinal chemistry.

[31]  Han Min Wong,et al.  Function and targeting of G-quadruplexes. , 2009, Current opinion in molecular therapeutics.

[32]  S. Basu,et al.  ILPR G-quadruplexes formed in seconds demonstrate high mechanical stabilities. , 2009, Journal of the American Chemical Society.

[33]  Carsten Kutzner,et al.  GROMACS 4:  Algorithms for Highly Efficient, Load-Balanced, and Scalable Molecular Simulation. , 2008, Journal of chemical theory and computation.

[34]  J. Šponer,et al.  Refinement of the AMBER Force Field for Nucleic Acids: Improving the Description of α/γ Conformers , 2007 .

[35]  L. Hurley,et al.  Biophysical studies of the c-MYC NHE III1 promoter: model quadruplex interactions with a cationic porphyrin. , 2007, Biophysical journal.

[36]  Shankar Balasubramanian,et al.  G-quadruplexes in promoters throughout the human genome , 2006, Nucleic acids research.

[37]  L. McGown,et al.  Insulin capture by an insulin-linked polymorphic region G-quadruplex DNA oligonucleotide. , 2006, Journal of the American Chemical Society.

[38]  Conrad C. Huang,et al.  UCSF Chimera—A visualization system for exploratory research and analysis , 2004, J. Comput. Chem..

[39]  Junmei Wang,et al.  Development and testing of a general amber force field , 2004, J. Comput. Chem..

[40]  L. Hurley,et al.  The dynamic character of the G-quadruplex element in the c-MYC promoter and modification by TMPyP4. , 2004, Journal of the American Chemical Society.

[41]  Christopher I. Bayly,et al.  Fast, efficient generation of high‐quality atomic charges. AM1‐BCC model: II. Parameterization and validation , 2002, J. Comput. Chem..

[42]  R. Glasspool,et al.  Telomerase and cancer: time to move from a promising target to a clinical reality , 2001, The Journal of pathology.

[43]  Berk Hess,et al.  GROMACS 3.0: a package for molecular simulation and trajectory analysis , 2001 .

[44]  W. Rutter,et al.  Unusual DNA structure of the diabetes susceptibility locus IDDM2 and its effect on transcription by the insulin promoter factor Pur-1/MAZ. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[45]  E. Ryan,et al.  Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. , 2000, The New England journal of medicine.

[46]  D G Myszka,et al.  Survey of the 1998 optical biosensor literature , 1999, Journal of molecular recognition : JMR.

[47]  P. Kollman,et al.  A Second Generation Force Field for the Simulation of Proteins, Nucleic Acids, and Organic Molecules , 1995 .

[48]  K. Docherty,et al.  The human insulin gene-linked polymorphic region adopts a G-quartet structure in chromatin assembled in vitro. , 1993, Journal of molecular endocrinology.

[49]  W. Rutter,et al.  Pur-1, a zinc-finger protein that binds to purine-rich sequences, transactivates an insulin promoter in heterologous cells. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[50]  R. Swendsen,et al.  THE weighted histogram analysis method for free‐energy calculations on biomolecules. I. The method , 1992 .

[51]  K. Docherty,et al.  The human insulin gene linked polymorphic region exhibits an altered DNA structure. , 1992, Nucleic acids research.

[52]  Bernard Pettitt,et al.  The potential of mean force surface for the alanine dipeptide in aqueous solution: a theoretical approach , 1985 .

[53]  W. Rutter,et al.  Polymorphic DNA region adjacent to the 5' end of the human insulin gene. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[54]  Charles H. Bennett,et al.  Efficient estimation of free energy differences from Monte Carlo data , 1976 .

[55]  K. Rajarathnam,et al.  Using isothermal titration calorimetry to determine thermodynamic parameters of protein-glycosaminoglycan interactions. , 2015, Methods in molecular biology.

[56]  S. Basu,et al.  ILPR repeats adopt diverse G-quadruplex conformations that determine insulin binding. , 2010, Biopolymers.

[57]  Stephen Neidle,et al.  Molecular modeling and simulation of G-quadruplexes and quadruplex-ligand complexes. , 2010, Methods in molecular biology.