Zhou Lab Research
Our group's research focuses on developing and utilizing statistical mechanics theories, bioinformatic, and simulation methods to explain and predict the behavior of biologically interesting macromolecules. The current research program aimed at the understanding of the molecular mechanisms and bioinformatic studies of protein folding, stability, and binding of ligands, peptides, and DNA. The long-term goal of the proposed research is to elucidate the relations between the sequence, structure, and function of proteins and to uncover the molecular mechanisms underlying different diseases. This will be accomplished by designing simple (yet realistic) models and by developing statistical mechanics theories and bioinformatic tools.
See Publications for Details

Protein Folding & Structure Prediction

Understanding the mechanism of folding and predicting folded structures are central problems in protein science. The solution of the protein folding problem is constrained by computing power. Atomic level models of proteins, built using an empirical force field (such as CHARMM), can be simulated in explicit solvent for only tens of nanoseconds, whereas protein folding (in vitro or in vivo) usually occurs on a time scale that is at least three orders of magnitude longer. My group addresses the computational challenge of developing models that are realistic enough to capture the folding behavior of a given protein and but are simplified for efficient calculations. We have developed a novel approach that employs square-well interactions to establish semi-realistic models. Preliminary studies show that this new all-atom model allows practical folding simulations using regular personal computers, and that it yields unprecedented accuracy in predicting the folding pathway(s) and identifying key residues of a given protein [48,50,53]. In particular, our results suggest that the mechanism of misfolding, as manifested in the formation of domain-swapped dimer, is largely determined by the native structure [50]. The new model will be further validated with experimental results and used for predicting the mechanism of folding and disease-causing misfolding. [ Movies on folding of a model all-beta protein]

Another challenge in theoretical studies of protein folding is the lack of accurate interaction potentials that serve to bias the native structure strongly against nonnative structures of proteins. We are developing a new reference-state method to extract atomic interactions from known protein structures. Preliminary studies suggest that the new method yields the best potential in recognizing native structures from decoys and in predicting mutation-induced changes in folding stability among all-atom knowledge-based potentials [52]. The initial success and productivity provide strong incentives for the further development and validation of the new method. The results will likely lead to more accurate methods for ab initio structure prediction as well as for high throughput structure determination with sparse NMR data.

Theoretical and Simulation Studies of Protein Binding

Unlike protein-solute interactions and protein-protein aggregations, the binding of a ligand to a protein or the binding between two proteins is highly specific. The high specificity of non-covalent binding between two macromolecules (molecular recognition) is critical in cellular assembly, gene expression, and signal transduction. Protein binding may accompany local (induced fit) and/or nonlocal conformational changes, the latter of which is often the source of binding cooperativity (allosteric effect) between different subunits. Allosteric interactions that regulate binding affinity occur when the binding of one ligand at a specific site is influenced by the binding of another ligand at a distant site. The regulation of binding events is essential for the orderly development of organisms and for effective response by organisms to changes in their environment. Aberrations in regulatory control processes are the causes for many diseases including cancer.

I am interested in developing an accurate theory of binding. The effect of electrostatic interactions on binding has been described by the Poisson-Boltzmann (PB) equation. Despite its success in many applications, the PB equation is limited to a fixed protein conformation in a dielectric continuum solvent. Our approach is to extend and develop statistical mechanics theories [32,37] that will incorporate the effects of the van der Waals and hydrogen-bonding interactions as well as molecular flexibility. An accurate theory of binding will be useful for the development of computational methods that aid structure-based drug design. One of the common approaches in drug design is to screen molecules that bind most to the active sites of proteins. The new theory should provide at least a semi-quantitative prediction of binding constants. In addition, the theory can be employed to study conformational changes upon binding and the role of electrostatics in ion selectivity and ion transport across a membrane.

Simulations using the all-atom CHARMM force field will be carried out to study protein dynamics, free energy changes due to mutations, and conformational changes. These studies with an all-atom realistic model will be complemented by those using the simpler models described above, so that both short and longer time-scale dynamics can be observed. The complementary roles of the simple model and the atomistic model are demonstrated in our recent work where the simulation of an all-atom representation of protein crambin quantitatively verified the results of a simple model in which the native state is a surface-molten solid state [38,47]. [ Movie on binding dynamics of a hemoglobin]

Representative publications

Y. Zhou, ``Salt effects on protein titration and binding.'', 102, 10615 (1998). [PDF]

Y. Zhou, D. Vitkup, and M. Karplus, ``Native proteins are surface-molten solids: Application of the Lindemann criterion for the solid versus liquid state.'', 285 , 1371 (1999). [PDF]

Y. Zhou and M. Karplus, ``Interpreting the folding kinetics of helical proteins.'', 401, 400-403 (1999). [PDF]

H. Zhou and Y. Zhou, ``Folding rate prediction using total contact distance.'', 82, 458--463 (2002). [PDF]

Y. Zhou and A. Linhananta, ``Thermodynamics of an all-atom off-lattice model of the fragment B of Staphylococcal protein A: Implication for the origin of the cooperativity of protein folding'', 106, 1481 (2002). [PDF]

A. Linhananta, H. Zhou and Y. Zhou, ``The dual role of a loop with low loop contact distance in folding and domain swapping'', 11, 1695 (2002).[PDF]

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