Three dimensional shape comparison of flexible proteins using the local-diameter descriptor

<p>Abstract</p> <p>Background</p> <p>Techniques for inferring the functions of the protein by comparing their shape similarity have been receiving a lot of attention. Proteins are functional units and their shape flexibility occupies an essential role in various biological processes. Several shape descriptors have demonstrated the capability of protein shape comparison by treating them as rigid bodies. But this may give rise to an incorrect comparison of flexible protein shapes.</p> <p>Results</p> <p>We introduce an efficient approach for comparing flexible protein shapes by adapting a <it>local diameter </it>(LD) <it>descriptor</it>. The LD descriptor, developed recently to handle skeleton based shape deformations <abbrgrp><abbr bid="B1">1</abbr></abbrgrp>, is adapted in this work to capture the invariant properties of shape deformations caused by the motion of the protein backbone. Every sampled point on the protein surface is assigned a value measuring the diameter of the 3D shape in the neighborhood of that point. The LD descriptor is built in the form of a one dimensional histogram from the distribution of the diameter values. The histogram based shape representation reduces the shape comparison problem of the flexible protein to a simple distance calculation between 1D feature vectors. Experimental results indicate how the LD descriptor accurately treats the protein shape deformation. In addition, we use the LD descriptor for protein shape retrieval and compare it to the effectiveness of conventional shape descriptors. A sensitivity-specificity plot shows that the LD descriptor performs much better than the conventional shape descriptors in terms of consistency over a family of proteins and discernibility across families of different proteins.</p> <p>Conclusion</p> <p>Our study provides an effective technique for comparing the shape of flexible proteins. The experimental results demonstrate the insensitivity of the LD descriptor to protein shape deformation. The proposed method will be potentially useful for molecule retrieval with similar shapes and rapid structure retrieval for proteins. The demos and supplemental materials are available on <url>https://engineering.purdue.edu/PRECISE/LDD</url>.</p

SHREC2020 track:Multi-domain protein shape retrieval challenge

Proteins are natural modular objects usually composed of several domains, each domain bearing a specific function that is mediated through its surface, which is accessible to vicinal molecules. This draws attention to an understudied characteristic of protein structures: surface, that is mostly unexploited by protein structure comparison methods. In the present work, we evaluated the performance of six shape comparison methods, among which three are based on machine learning, to distinguish between 588 multi-domain proteins and to recreate the evolutionary relationships at the proteinand species levels of the SCOPe database. The six groups that participated in the challenge submitted a total of 15 sets of results. We observed that the performance of all the methods significantly decreases at the species level, suggesting that shape-only protein comparison is challenging for closely related proteins. Even if the dataset is limited in size (only 588 proteins are considered whereas more than 160,000 protein structures are experimentally solved), we think that this work provides useful insights into the current shape comparison methods performance, and highlights possible limitations to large-scale applications due to the computational cost

SHREC 2018 - Protein Shape Retrieval

Proteins are macromolecules central to biological processes that display a dynamic and complex surface. They display multiple conformations differing by local (residue side-chain) or global (loop or domain) structural changes which can impact drastically their global and local shape. Since the structure of proteins is linked to their function and the disruption of their interactions can lead to a disease state, it is of major importance to characterize their shape. In the present work, we report the performance in enrichment of six shape-retrieval methods (3D-FusionNet, GSGW, HAPT, DEM, SIWKS and WKS) on a 2 267 protein structures dataset generated for this protein shape retrieval track of SHREC’18

Spherical harmonics coeffcients for ligand-based virtual screening of cyclooxygenase inhibitors

Background: Molecular descriptors are essential for many applications in computational chemistry, such as ligand-based similarity searching. Spherical harmonics have previously been suggested as comprehensive descriptors of molecular structure and properties. We investigate a spherical harmonics descriptor for shape-based virtual screening. Methodology/Principal Findings: We introduce and validate a partially rotation-invariant three-dimensional molecular shape descriptor based on the norm of spherical harmonics expansion coefficients. Using this molecular representation, we parameterize molecular surfaces, i.e., isosurfaces of spatial molecular property distributions. We validate the shape descriptor in a comprehensive retrospective virtual screening experiment. In a prospective study, we virtually screen a large compound library for cyclooxygenase inhibitors, using a self-organizing map as a pre-filter and the shape descriptor for candidate prioritization. Conclusions/Significance: 12 compounds were tested in vitro for direct enzyme inhibition and in a whole blood assay. Active compounds containing a triazole scaffold were identified as direct cyclooxygenase-1 inhibitors. This outcome corroborates the usefulness of spherical harmonics for representation of molecular shape in virtual screening of large compound collections. The combination of pharmacophore and shape-based filtering of screening candidates proved to be a straightforward approach to finding novel bioactive chemotypes with minimal experimental effort