Protein Motion and Docking

The goal of protein docking research aims to determine the particular binding interaction between two molecules. Current approaches generally assume that the two interacting bodies are rigid; that is, docking is attempted by exploring translational and rotational configurations of the two molecules. However, a protein often has some degree of flexibility, and often such internal flexibility is in fact a crucial component of a docking process. For example, a flexible flap region of HIV-1 protease clamps down upon the binding site so as to secure the viral precursor cells and facilitate the enzymatic reaction. Without the movement of the flaps, HIV-1 protease cannot fulfill its enzymatic function, and therefore any accurate docking prediction algorithm needs to incorporate and consider the internal motion of HIV-1 protease.

In developing an efficient docking program, we aim to build a protein model which is amenable to quick and efficient computational methods. We represent a protein as a kinematic robotic arm, which serves as a platform for the application of forces, after which we then can calculate the ensuing internal and external protein motions. The kinematic constraints imposed on the protein robot model act to reduce the conformational space of the protein, and hence sampling as well and prediction calculations are quicker than when the entire conformation space has to be considered.

Shown: A robotic model of the backbone and partial sidechains of HIV-1 Protease and the movement resulting from the motion of the upper flaps towards the binding site situated in the interior of the protein cleft. The blue lines depict various hydrogen bonds which constrain the structure of the protein and subsequently moderate the ensuing movement.


This work is funded in part by NSF grant number 0622115 in the EMT program, NSF grant number 0551500 in the CRI program, and NIH NIGMS grant number 1R01GM076706 in the CST program.

Publications

Lee, Audrey, Ileana Streinu, and Oliver Brock. A Methodology for Efficiently Sampling the Conformation Space of Molecular Structures. Physical Biology 2:S108-S115, November 2005. html pdf

Lee, Audrey, Oliver Brock, and Ileana Streinu. A Methodology for Efficiently Sampling the Conformation Space of Molecular Structures. Technical Report 05-40. Computer Science Department, University of Massachusetts Amherst, July 2005. pdf

Filip Jagodzinski
AudreyLee
IleanaStreinu
OliverBrock