The
group of Professor Tamar Schlick, housed at the Chemistry
Department and the Courant
Institute of Mathematical Sciences at NYU
, is made up of postdoctoral fellows and students with diverse backgrounds,
including mathematics, computer science, physics, chemistry, and biology.
Our current research aims to understand how the structures and motions of complex biological systems regulate fundamental functions like DNA transcription, replication, and recombination and the initiation of disease (e.g., by replication errors or misfolding of proteins). We develop and apply simulation approaches (molecular dynamics, energy minimization, free energy calculations, general molecular modeling) to allow large-scale and long-time studies of biological systems to help interpret experiments with systematic, quantitative information on energetics and reaction kinetics that is difficult to obtain experimentally. Such information offers new insights into the fundamental relationship among sequence, structure, and biological function. Our interdisciplinary group includes undergraduate students, graduate students, postdoctoral fellows, and collaborators from varied backgrounds in the mathematical/physical and biological disciplines.
Specifically, we are focusing on DNA/protein interactions
in fundamental regulatory processes that occur over a range of spatial
and temporal scales; such interactions control gene expression, genome
packaging, replication, repair, recombination, etc.
[Jones et al., 1999;
Bloomfield et al., 2000;
Fersht, 1999; Branden
& Tooze, 1999] . Modeling these systems can complement instrumentation
and suggest new experiments. Indeed, macromolecular modeling now has potential
to be ahead of experiment (e.g., structural genomics, supramolecular complexes,
neurobiology) rather than serve as `complement'.
Two experimental collaborations launched in early 1999,
involving transcription and DNA synthesis, exemplify our interests
[Qian et al., 2001;
Yang et. al., 2001]. They involve
studies of the relationship between TATA-box variants and TBP (TATA-box
binding protein) binding and activity, and kinetics of DNA polymerase function
in DNA repair. Crystals of these DNA/protein systems (from Steve Burley
[Patikglou et al., 1999] and Sam
Wilson [Sawaya et al., 1997]),
together with other experimental measurements, posed intriguing questions
-- regarding diverse transcription activities of TATA variants that differed
by one base pair, and the nature of the slow conformational rearrangements
before/after the chemical step in the catalytic cycle of DNA replication
and repair synthesis. Our simulations provided some answers by demonstrating
DNA sequence propensities that affect TBP binding/activity [Qian
et al., 2001; Strahs &
Schlick, 2000] and by dileneating kinetic
aspects of polymerase's DNA synthesis, including a rate-limiting Arg258
rotation, that may help explain fidelity aspects [Yang et al., 2001].
These ambitious studies were tractable largely due to our efficient integrator
LN [Barth & Schlick, 1998a],
[Schlick & Yang, 2001;
Schlick, 1998; Sandu
& Schlick, 1999; Schlick,
2001] and economical periodic boundary models
[Qian et al., 2000].
The TATA and polymerase works represent microscopic studies. Ultimately, we are interested in bridging [Schlick et al., 2000] all-atom studies (e.g., amplification of DNA's intrinsic deformability in DNA/protein interactions [Dickerson, 1998; Crothers, 1998; Schildbach et al., 1999; Olson et al., 1998] , or motion details [Yang et al., 2001]) with macroscopic aspects of cellular networks (e.g., eukaryotic transcription). This requires hierarchical studies approaching macroscopic levels. Therefore, we study in tandem closely-related problems for long DNAs with multiple proteins, like chromatin folding [Beard & Schlick, 2001a] and large-scale site juxtaposition in supercoiled DNA [Jian et al., 1998; Huang et al., 2001] . For example, our studies on the interactions that stabilize chromatin [Roychoudhury et al., 2000] are related to chromatin remodeling/modification (related to DNA supercoiling) and its affect on transcription regulation [Kahn et al., 2000], DNA replication and recombination [Wolffe, 1998; Kornberg & Lorch, 1999] , viral infection and cancer (e.g., by polymerase errors) [Friedberg et al., 2000].
Our other recent research interests include genomics and drug design -- areas where new algorithms are critically needed. We work on protein structure prediction by ab initio methods [Gan et al., 2000; Gan et al., 2001b] bioinformatics sequence/structure/function in proteins) [Gan et al., 2001a], and combinatorial chemistry and drug design [Xie et al., 2000; Xie & Schlick, 2000; Xie et al., 2001] .
