Research

Our interests lie at the interface between theoretical/computational chemistry and biophysics. The current research in the lab is directed towards understanding how biomolecules perform their functions via dynamical motions that are encoded in their three dimensional structures. Ongoing projects include computer simulations of ABC-transporters and development of combined quantum mechanical/molecular mechanical (QM/MM) methods.

ABC-transporters

Maltose transporter from E. coli

Many essential functions of living cells are performed by nanoscale motors consisting of protein complexes. The ability of these biomolecular motors to utilize chemical free energy to perform mechanical work makes them splendid molecular machines. Among various types of molecular motors, ATP-binding cassette (ABC) transporters represent a unique family of motor proteins that enable translocations of various substrates across cell membranes, by harnessing the free energy associated with ATP binding and hydrolysis. Dysfunctions of ABC-transporters have been linked to a number of diseases, including cystic fibrosis, the most common fatal hereditary disease in the US. The over expressions of certain ABC-transporters are also known to contribute to multidrug resistance of tumor cells after cancer patients receive chemotherapy. Making using multiscale computer simulations, our project aims at obtaining a deeper understanding of conformational dynamics, enzyme catalysis, as well as the chemomechanical coupling mechanisms under which the chemical free energy is converted into mechanical work in ABC-transporters. Currently, we are focusing on elucidation of ATP hydrolysis mechanisms in several ABC proteins.

DNA damages

SP lesion in DNA

In scarce of nutrients and lack of suitable conditions for replication, some bacteria form endospores, which protect bacterial DNAs from various environmental damaging factors, including UV radiations. Under regular cellular conditions, UV radiation causes adjacent Thymines (TT) bases in DNA to be cross-linked, forming the dominant cyclopyrimidine dimer (CPD) lesions. In spores, the DNA photoreaction pattern is altered such that an atypical lesion, 5-thyminyl-5-6-dihydrothymine, commonly known as the spore-photoproduct (SP), becomes the most prevalent form of TT damages. The formation of SP lesions is postulated to “lock” the spore DNAs to an chemically inert state in a well-controlled manner until spores progress to the germination phase, during which the SP lesions are repaired faithfully by a spore enzyme called spore-photoproduct lyase (SPL). Despite this generally accepted scheme, the precise mechanisms of how SP lesions is promoted from a minor to a dominant product in spores as well as how SP is recognized by the repair enzyme SPL remain largely unknown. Collaborating with Prof. Lei Li, we have computationally characterized a dinucleotide analog of SP and currently we are simulating short segments of DNA containing the SP lesion.

QM/MM development

The IPS method: interactions are computed explicitly up to a cutoff distance Rc. Beyond that an average potential is used.

We are exploring new approach to include long-range electrostatic interactions in combined quantum mechanical and molecular mechanical (QM/MM) calculations. Traditionally, long-range electrostatics in molecular simulations can be treated by lattice sum methods such as the Ewald method, where Coulomb interactions are collected over periodic systems in a manner that contributions from all particles as well as their periodic images are included without any truncation. The Isotropic Periodic Sum (IPS) method provides an efficient alternative to Ewald such that the pairwise interactions are only computed in a local region, where beyond this cutoff distance of the local region, the long range contribution is represented in a mean field fashion by assuming an isotropic distribution of image particles. The IPS method and has been developed and applied to classical systems including biomolecules and ionic systems . We are currently developing computer code to extend the IPS method to treat systems that are described by combined QM/MM potentials.