Research

Welcome to the York Group research page. Choose from the active links below to access information about:

Research Overview - a brief overview of the York Group research.
Software - browse some of the in-house software
Databases - peruse several of the quantum databases under construction
Galleries - collections of research-related figures and movies

Research Overview

The York Group research involves the development of a broad range of theoretical methods aimed, ultimately, at providing the computational biology community with improved tools for the simulation of biological reactions. The main application focus of the group is the study of the molecular mechanisms of RNA catalysis. The study of RNA catalysis is important from a fundamental biological perspective and has potential impact to aid the design of new medical therapies that target genetic disorders and biotechnology that uses RNA molecules as allosteric molecular switches.

Currently, the lab is concentrated on the study of phosphoryl transfer reactions in non-enzymatic and enzymatic environments. Two RNA enzyme (ribozyme) systems are under study: the hammerhead ribozyme and the hairpin ribozyme. These RNAs are ideal prototype systems for theoretical study due to their small size and wealth of available experimental structural and kinetic data. Despite the tremendous amount of experimental effort, the molecular mechanisms of these RNA enzymes remain a topic of considerable debate.

From a theoretical perspective, ribozymes present several features that make them difficult to model relative to most proteins. RNA is inherently highly charged and interacts strongly with monovalent and divalent metal ions and solvent. Careful treatment of long-range electrostatics is critical, as is the inclusion and equilibration of a sufficiently extensive solvation and ion atmosphere. The importance of quantum many-body effects such as polarization and charge transfer, which are neglected in conventional molecular mechanical force fields, is amplified in RNA simulations. RNA exhibits a greater degree of conformational variation than most proteins, and experimental structural data is often more difficult to acquire, especially in solution. Reliable molecular simulations of RNA, therefore, need to take into account extensive conformational sampling. Finally, the chemistry of many RNA-catalyzed reactions, such as transphosphorylation and phosphate hydrolysis, involves ionic interactions, large polarization effects and transitions between tri-, tetra- and pentavalent phosphorus that require an accurate d-orbital quantum model for a proper description.

The end goal of the theoretical work is to develop methods that allow simulation of catalytic RNA systems to be performed with increased reliability and predictive capability. For this reason, the research in the York Group is focused on the design of new multi-scale quantum models to study phosphoryl transfer reactions in non-enzymatic and enzymatic environments. Here, ``multi-scale'' implies the integration of a hierarchy of methods that span a broad range of spatial and temporal domains, and work together in concert to provide insight into complex problems.

This, then, is the main objective of the York Group research: to design and apply new multi-scale quantum models to the problem of RNA catalysis, in particular, ribozyme-catalyzed phosphoryl transfer reactions. The main premise is that new multi-scale methods need to be designed that simultaneously provide high accuracy and efficiency for complex reactions that involve biological phosphorus.

At one end of the spectrum are fast molecular simulation methods that can be improved by development and testing of new-generation many-body force field models. At the other end of the spectrum are linear-scaling electronic structure methods that can be made faster and more accurate with the design of new semiempirical quantum models for biological reactions. At the interface are hybrid quantum mechanical/molecular mechanical (QM/MM) methods that rely on both the force field and electronic structure methods in addition to methods related to the treatment of the solvent and macromolecular environment. The relation between the multi-scale quantum methods that are being developed in the York Group and applied to the problem of RNA catalysis are illustrated in Scheme 1.

Scheme 1. Multi-scale quantum models developed in the York Group to study RNA catalysis. Here ``Non-linear optimization'' refers to a suite of algorithms for optimization of parameters used in the semiempirical models and new-generation many-body force fields. With the exception of the ``Experimental data'', the linked schematic bubbles refer to original research contributions of the York Group.

The design of new theoretical methods for RNA catalysis in the York Group include:

Linear-scaling electronic structure methods

Extension of theory to macromolecular problems requires computational methods that are efficient and have well behaved scaling properties. Conventional density-functional theory (DFT) and Hartree-Fock methods are limited to fairly small systems since the computational effort scales as the cubic of the number of atoms (or higher), making application of these methods to macromolecular systems unfeasible. The main scaling bottlenecks arise from (1) the order N³ problem of maintaining orthogonality of molecular orbitals (or equivalently the idempotency condition of the single-particle density matrix) in accord with the Pauli exclusion principle, and (2) the order N² problem of calculating long-range Coulomb interactions. The latter problem can be surmounted with fast-multipole techniques or linear-scaling Ewald methods that are also applicable in other important areas of computational chemistry such as molecular simulation and implicit solvation methods. A focus of the lab is to develop new "linear-scaling" electronic structure methods that are able to treat very large systems, and to apply them to exciting new areas such as the study of quantum mechanical effects on biological macromolecules in solution.

Recently it has become possible to perform fully self consistent electronic structure calculations of biological macromolecules up to 10,000 atoms in solution at the semiempirical level. It is a primary focus of the lab to extend these techniques to ab initio (Hartree-Fock and density-functional) methods, and apply them to important biological and pharmaceutical problems such as the elucidation of quantum mechanical electrostatic potential surfaces and reactivity indexes, pKa shifts, density of electronic states, and the role of solute polarization in the process of solvation and ligand binding. More complex problems such as enzyme catalysis and long-range electron transfer events in biological macromolecules are areas of intense interest, and complimented by the molecular simulation and hybrid QM/MM component of the group's research.

In order to develop quantum models that are both highly accurate and sufficiently fast for application of linear-scaling and hybrid QM/MM calculations of catalytic RNA systems, a large database of biological phosphates, phosphoranes and phosphoryl transfer reactions was constructed. The database of Quantum Calculations for RNA (QCRNA), has recently come on-line and is open to the public. The database contains over 1,500 molecular structures and complexes and over 200 reaction mechanisms, all calculated with a strict, consistent high-level density-functional protocol. Construction of the database was a tremendous undertaking and an essential step in the development of robust, highly accurate quantum models for RNA catalysis. The model structures, complexes and reactions in the database are of considerable biological importance and interest by themselves, and to date, publications have resulted on the structure and stability of biological phosphates and phosphoranes including binding with divalent Mg(II) ions, pseudorotation barriers of chemically modified phosphoranes, and in-line attack mechanisms of phosphate hydrolysis and thio effects.

Molecular simulation is a powerful tool for examining the dynamic behavior of molecular systems and chemical processes. Unfortunately, the computational requirement inherent in even the most efficient ab initio methods precludes their application to simulations of very large systems in the near future. For these systems, approximate methods that are less computationally demanding are required. An area of active research involves the development of improved physical models that reliably describe molecular interactions with minimal parameters and computational overhead.

Recently, a new model for polarization and charge transfer has been introduced that utilizes the electron density as the basic variable and takes into account many-body effects. The generalized chemical potential equalization (CPE) method is a density-functional based approach for inclusion of many-body polarization effects in molecular simulations. The method incorporates quantum chemical properties such as electronegativity and hardness based on their mathematical definitions founded in density-functional theory, and requires minimal overhead relative to conventional force field methods.

A long term objective of the lab is to develop a new generation force field for molecular simulations of biomolecules that includes many-body effects and can be rigorously combined with higher level ab initio methods to produce hybrid potentials (see below). The force field will involve modification of standard electrostatic point charge terms to include nuclear terms and smooth electron density distributions. These distributions can adjust (polarize) according to the CPE equations to allow a dynamical description of the charge density as a function of conformation and molecular environment.

Applications involving complex chemical reactions ultimately require the rigor afforded by high level first-principle methods. Fortunately, regions where chemical bond cleavage and formation occur, such as the active site of an enzyme, typically account for only a relatively small portion of the total system. An attractive strategy for attacking very large problems involves combining quantum mechanical (QM) and molecular mechanical (MM) models.

Unfortunately, the computational cost of sufficiently accurate ab initio or density-functional methods often preclude their application to complex mechanistic paths that require extensive configurational sampling. More efficient quantum models, such a semiempirical models, are sufficiently fast; however, there currently exists no semiempirical methods that are able to reliably model phosphate hydrolysis reactions. To remedy this problem, we have constructed an extensive density-functional quantum database for phosphate hydrolysis reactions using small molecule models. We have built a program for non-linear semiempirical parameter optimization against the database in order to derive reliable semiempirical parameters for phosphate hydrolysis reactions that can be applied in hybrid QM/MM calculations to the important ribozyme systems.