Theoretical physical chemistry and molecular biophysics, quantum mechanics, statistical
thermodynamics, molecular dynamics and Monte Carlo computer simulation; structure,
dynamics and solvation of nucleic acids and proteins, role of water in structural
biochemistry.
The biological functions of DNA-information storage, replication, and
transcription-are ultimately linked to the chemical elements of energetics,
structure, and molecular motions. Understanding and interpreting the
experimental results requires molecular models that are consistent with observed
data. Molecular dynamics (MD) computer simulation is a quantitative,
deterministic technique available for modeling macromolecular systems, and in
principle produces a complete microscopic description of the molecular structure
and motions of proteins, nucleic acids, and other macromolecules. In practice,
MD modeling of DNA is a work in progress, with results mitigated by
approximations in the underlying empirical force field, simulation protocols,
system preparation, and digital computer capacity. Recent developments,
particularly "second generation" force fields designed for use with explicit
solvent models, treatment of long range interactions using the particle-mesh
Ewald method, and advances in PC Cluster technology, have combined to produce
considerably more accurate MD models of DNA than those obtained with first
generation methods. These developments position MD modeling at a vantage point
to make important and timely contributions to the structural biology of nucleic
acids. Specific problems we are concerned with are:
- Characterization Studies on DNA and RNA oligonucleotides: MD
simulations on oligonucleotide sequences, well-characterized experimentally,
form a basis for assessments of MD methods as well as investigations into the
nature of the dynamical structures. Studies of a broad range of systems
involving diverse sequences in both solution and crystalline conditions are
required to fully elaborate this problem area, and focusing on failures or
limitations of the methodology is essential to determine where improvements
need to be made. The development of general procedures for comparison of MD
modeling results systematically with experimental results from crystallography
and NMR spectroscopy is a part of this initiative.
- DNA and RNA Solvent Effects: MD studies in this problem area are
divided into two sub-areas: a) the effect of water, counterions, and coions on
nucleic acid structure and b) the effect of nucleic acids on the structure of
water, counterions and coions. Patterns in the structure of water and ion
atmosphere around DNA are delineated and compared with available data to
assess the accuracy of the solvent models, residence times, and other
dynamical elements of water and mobile ions. The development of methods for
estimating solvation free energies from simulation is important to future
developments in the field.
- Sequence Effects on DNA Structure and Axis Bending: MD models of
the structure and motions of all 10 unique base-pair steps will serve as a
basis for inquiring as to whether the average helicoidal parameters
incorporated in a dinucleotide regression model can account for the variance
in the experimental data such as gel retardation related to DNA bending. This
project will be extended to consider context effects and each step will be
analyzed with respect to solvation structure and the water and ion residence
times to investigate further sequence dependent YR and RY steps and to explain
the results in terms of a trade-off between steric clashes and hydrophobic
penalties on unstacking. We participate in a consortium designed to produce MD
models of all base pair quadruples in order to study context effects on
structure.
- DNA and RNA Recognition and Ligand Binding: We are in the process
of intensive MD studies of a small selection of DNA-drug, DNA-protein, and
RNA-protein complexes. Specific issues we are interested in are the problems
of structural reorganization and adaptation of nucleic acid and ligand in
binding, the nature of counterion reorganization and release on complex
formation, and the entropic effects on complex formation related to the
conversion of rotational and translational degrees of freedom into low
frequency vibrations. These studies all relate to the functional energetics of
ligand binding, and emphasize aspects uniquely accessible to MD simulation. In
parallel, we are concerned with the prospects of a general unified theory of
molecular and macromolecular ligand binding to DNA and RNA and the difficult
problems and limitations of computational theory in the sector.
- MD Simulations, Hidden Markov Models, and Structural Genomics: MD
studies of DNA provide a potentially novel vantage point on the field of
structural genomics. Experiments such as gel retardation and cyclization
kinetics measure a combination of the properties of curvature, bending, and
bendability, impossible to deconvolute since there is no unequivocal molecular
model for the process. From MD these properties can be deconvoluted by step.
We are pursuing the idea that probabilistic measures of DNA deformations of
various sorts from MD can be used as a basis for Hidden Markov Models and used
to identify structural homologies in genomic problems. If successful, the
resulting HMMs will provide a tool for genomics research with the potential to
score properly on structural as well sequence characteristics. HMM/MD
methodology is expected to be particularly useful in elucidating multiple
binding sites of regulatory proteins and in exploring the nature of direct and
indirect readout in protein DNA and RNA recognition.
Selected Publications
- Jayaram, B., K. McConnell, et al. (2002). "Free-energy component analysis
of 40 protein-DNA complexes: A consensus view on the thermodynamics of binding
at the molecular level." Journal of Computational Chemistry 23(1): 1-14.
- Liu, Y.X. and D.L. Beveridge (2002). "Exploratory studies of ab initio
protein structure prediction: Multiple copy simulated annealing, AMBER energy
functions, and a Generalized Born/Solvent Accessibility solvation model."
Proteins-Structure Function and Genetics 46(1): 128-146.
- "Pitici, F., D. L. Beveridge, et al. (2002). "Molecular dynamics simulation
studies of induced fit and conformational capture in U1A-RNA binding: Do
molecular substrates code for specificity?" Biopolymers 65(6): 424-435.
- "Thayer, K. M. and D. L. Beveridge (2002). "Hidden Markov models from molecular
dynamics simulations on DNA." Proceedings of the National Academy of Sciences
of the United States of America 99(13): 8642-8647.
- "Beveridge, D. L., S. B. Dixit, et al. (2004). "Molecular dynamics of DNA and
protein-DNA complexes: Progress on sequence effects, conformational stability,
axis curvature, and structural bioinformatics." Nucleic Acids: Curvature and
Deformation 884: 13-64.
- "Beveridge, D. L., S. B. Dixit, et al. (2004). "Molecular dynamics simulations
of DNA curvature and flexibility: Helix phasing and premelting." Biopolymers
73(3): 380-403.
- "Byun, K. S. and D. L. Beveridge (2004). "Molecular dynamics simulation of
papilloma virus E2 DNA sequences: Dynamical models for oligonucleotide
structures in solution." Biopolymers 73(3): 369-379.
- "Ponomarev, S. Y., K. M. Thayer, et al. (2004). "Ion motions in molecular
dynamics simulations on DNA." Proceedings of the National Academy of Sciences
of the United States of America 101(41): 14771-14775.
- "Beveridge, D.L., Barreiro, G. et al. (2004) “Molecular Dynamics Simulations of
the 136 Unique Tetranucleotide Sequences of DNA Oligonucleotides. I. Research
Design and Results on d(cpG) Steps.” Biophysical Journal (87): 1-15.
- Thayer, K.M. and Beveridge, D.L. (2004) "MD-based DNA binding site tools
identify CAP target sites using direct and indirect readout." Biophysical
Journal 86(1): 416A-416A.
- Beveridge, D.L. (2004) "Nucleic acid science articles - Preface."
Biopolymers 73(3): 326-326.
- Knee, K.M., Aitken, C.E., Beveridge D.L. et al. (2005) "Theoretical and
Experimental Evidence for a Sequential Mechanism for the DNA B ->A Transition."
Biophysical Journal 88(1): 58A-59A.
- Dixit, S.B. Andrews D.Q., Beveridge, D.L. et al. (2005) "Induced Fit an the
Entropy of Structural Adaptation in the Complexation of CAP and
Lambda-Repressor with Cognate DNA Sequences," Biophysical Journal 88(5):
3147-3157.
- Dixit, S.B, Beveridge, D.L. (2005) "Axis Curvature and Ligand Induced
Bending in the CAP-DNA Oligomers." Biophysical Journal 88(1): L4-L6.
- Dixit, B.
S., Beveridge, D.L., et al. (2005) “Molecular Dynamics Simulations of the
136 Unique Tetranucleotide Sequences of DNA Oligonucleotides. II: Sequence
Context Effects on the Dynamical Structures of the 10 Unique Dinucleotide
Steps,” Biophysical Journal 89: 3721-3740
- Dixit, S.B., Andrews, D.Q., and Beveridge, D.L., (2005) "Induced fit and
the entropy of structural adaptation in the complexation of CAP and
lambda-repressor with cognate DNA sequences," Biophys J. 88 (5):
3147-57.
- Zhao, Y., et al. (2006) "Molecular dynamics simulation studies of a
protein-RNA complex with a selectively modified binding interface,"
Biopolymers 81 (4): 256-69.
- Dixit, S.B., Ponomarev, S.Y., and Beveridge, D.L., (2006) "Root Mean Square
Deviation Probability Analysis of Molecular Dynamics Trajectories on DNA,"
American Chemical Society, Published on Web, EST: 9.5.
- Dixit, S.B., Ponomarev, S.Y., and Beveridge, D.L., (2006) "Root Mean Square
Deviation Probability Analysis of Molecular Dynamics Trajectories on DNA,"
J Chem Inf Model, 46, 1084-1093.
- Dixit, S.B, and Beveridge, D.L, (2006) "Structural bioinformatics of
DNA: a web-based tool for the analysis of molecular dynamics results and
structure prediction," Bioinformatics Applications Notes, Vol. 22 (8)
1007-1009.
- Kormos, B.L., Baranger, A.M., and Beveridge, D.L. (2006) Do collective
atomic fluctuations account for cooperative effects? Molecular dynamic
studies of U1A-RNA complex. J AM Chem Soc, 128, 8992-8993.
- Kormos, B.L., Baranger, A.M., and Beveridge, D.L. (2007) A Study of
collective atomic fluctuations and cooperativity in the U1A-RNA complex
based on molecular dynamics simulations. J. Struc. Biol., 157,
500-513.
- Yan, Z. et. al. and Beveridge, D.L. (2007) Identification of an
aminoacidune derivative that binds to RNA tetraloops. J. Med. Chem.,
50:4096-104.
- Annunciado, D., et. al. Knee, J.L and Beveridge, D.L. (2008)
Characterization of the dynamics of an essential helix in the U1a protein by
time-resolved fluorescence measurements. J. Phys. Chem. B.,
112:6122-30.
- Knee, K.M., et. al. and Beveridge, D.L. (2008) Spectroscopic and
molecular dynamics evidence for a sequential mechanism for the A-to-B
transition in DNA. Biophys. J., 95: 257-72.
Education
- B.A. 1959 College of Wooster, Ohio
- Ph.D. 1965 University of Cincinnati
- Theoretical physical chemistry
- Postdoctoral Fellowships:
- Centre de Mécanique Ondulatoire Appliqué Paris, France;
- Carnegie Mellon University
[Chemistry] [Wesleyan]
Last updated: July 15, 2009 (DLB/rncb)
