Integrating Rigidity Analysis into the Exploration of Protein Conformational Pathways Using RRT* and MC

Abstract

To understand how proteins function on a cellular level, it is of paramount importance to understand their structures and dynamics, including the conformational changes they undergo to carry out their function. For the aforementioned reasons, the study of large conformational changes in proteins has been an interest to researchers for years. However, since some proteins experience rapid and transient conformational changes, it is hard to experimentally capture the intermediate structures. Additionally, computational brute force methods are computationally intractable, which makes it impossible to find these pathways which require a search in a high-dimensional, complex space. In our previous work, we implemented a hybrid algorithm that combines Monte-Carlo (MC) sampling and RRT*, a version of the Rapidly Exploring Random Trees (RRT) robotics-based method, to make the conformational exploration more accurate and efficient, and produce smooth conformational pathways. In this work, we integrated the rigidity analysis of proteins into our algorithm to guide the search to explore flexible regions. We demonstrate that rigidity analysis dramatically reduces the run time and accelerates convergence.

Using Topological Data Analysis and RRT to Investigate Protein Conformational Spaces

“…It builds a tree rooted at the start configuration and grows by using random samples from the exploration space and connecting them to the closest vertex in the tree. We used this algorithm in our previous efforts, [14,15] to explore the conformational space of proteins. Here is a quick review of the basic algorithm: At every iteration, the algorithm generates a random conformation q rand , finds the closest node to q rand in the tree, and tries to create a path from the closet node found to the q rand .…”

“…Previous Work: In our previous work [14], we focused specifically on rigidity analysis information and extracted the flexible residues. We used this information to lead the search by using flexible hinges to manipulate.…”