Research Interests

Introduction

The work of the cell machinery is ultimately carried out through the actions of biomolecules. In a sense, these molecules provide a bridge between the non-living and the living. An individual biomolecule, protein or nucleic acid, is itself a complex system but unlike other large chemical compounds their rich characteristics are an outcome of evolutional selection. The physical properties of these molecules, which are key to their biological function, are often described by their energy landscape.

We are focused on advancing our understanding of biomolecules (the sequence-structure-function problem) using a battery of computational and theoretical methods that capture their chemical and physical nature as well as the billions of years of evolutional design. Our main aim is to decipher the complexity of proteins and nucleic acids that results in self-recognition and cellular communication and therefore a biological function. Unraveling mysteries on the structure, assembly, and interactions at the molecular level have long-term implications for combating medical conditions such as Creuzfeld-Jacob (Mad Cow disease), Alzheimer, and cancer.

 

Protein Folding and Post-translational Modifications

Protein folding has long been viewed as being rich in complexities. With the development of the energy landscape theory, our view of protein folding, however, has greatly simplified from the hopelessly complex one first presented by Levinthal’s paradox. Because of their funneled energy landscapes, global structural measures of similarity to the native state are clearly adequate for describing the folding progression for most natural proteins. Quantifying the energetic and entropic competition, which is pivotal to any folding reaction, is still sometimes not sufficient. We are interested in studying fundamental questions of the mechanisms of protein folding and to formulate the forces that bias an efficient folding. While most efforts in folding research have focused in recent year on small proteins, exploring the folding of larger proteins is of high interest. Additionally, studying anomalous folding phenomena may serve to understand the rule. As an example, we may mention the remarkably diverse folding kinetics of some structurally homologous proteins. Finally, often proteins undergo posttranslational modifications that are important to regulate their function. We study the effects of these modifications on the protein thermodynamics and kinetics.

 

Protein-Protein Assembly

Biomolecules rarely function in isolation, hence a thorough understanding of biological processes is dependent upon an examination of complexes of biomolecules, and the interactions between complexes. For example, large-scale motions occur and are often essential for biomolecule function, especially with regard to proteins. Theoretical approaches developed for folding which incorporate the interplay between energetics and configurational entropy can now be utilized to study protein function. Discovering the physical and molecular aspects of protein binding underpins the understanding of all cellular functions.

Protein recognition and binding, which result in either transient or long-lived complexes, play a fundamental role in many biological functions, but sometimes also result in pathologic aggregates. Using simplified simulation models, we survey a range of systems where two highly flexible protein chains form a homodimer. Owing to the minimal frustration principle, we find that, as in the case of protein folding, the native topology is the major factor that governs the choice of binding mechanism. In all cases, the model that corresponds to a perfectly funneled energy landscape for folding and binding, reproduces the macroscopic experimental observations on whether folding and binding are coupled in one step or whether intermediates occur. Even when the monomer is stable on its own, binding sometimes occurs fastest through unfolded intermediates thus showing the speedup envisioned in the fly-casting scenario for molecular recognition.

We focus on understanding mechanisms of protein association and the degree of protein plasticity involved in these reactions. Quantifying the capacity of a protein to bind to other specific proteins is also crucial to understand the networks of protein interaction. Deciphering the key steps in protein self-assembly has practical applications for designing medications. Instead of targeting a single molecule in the cell, more effective pharmaceuticals would eradicate a pathogen’s complete network, obstructing harmful assemblies of proteins that are the cause of many neurodegenerative diseases such as Creuzfeld-Jacob and Alzheimer.

 

Protein-DNA recognition

Essentially, most of the biological functions of DNA require the binding of specific proteins to specific DNA sequences. For binding to occur, the protein has to discriminate between many similar and competing binding sites. It must not only recognize the DNA site, but also find the appropriate target rapidly, and tightly bind to one having the special features and corresponding biological function that distinguishes it from the millions of competing and overlapping non-specific sites.

We focus on deciphering the mechanisms and kinetics of DNA recognition by monomeric and multimeric proteins with the ultimate goal of understanding cellular communication from physical and molecular viewpoints using theoretical and computational tools. Quantifying the molecular and physical principles of the mechanisms of protein-DNA assembly is key to cracking down the protein-DNA recognition code and improving the prediction of specificity and binding affinity.

Computer-based models will aid in understanding the movement and mechanisms of protein assembly on DNA. Advancing the molecular mechanism of DNA search by proteins is not only vital to understanding the cellular machinery and the products of the information stored on the genome sequence, but it can also yield many practical applications. Computational model can aid in investigating how mutations in the p53 protein lead to cancerous growths by directly or indirectly affecting the assembly of the protein subunits and their interactions with DNA. Theoretical studies of such key events in cellular life and death may suggest approaches for designing drugs that will restore the network of interactions of p53 that allow it to act as a guardian of the genome and prevent the malignancies.