Delineating Conformational Variability in Small Protein Structures Using Combinatorial Refinement Strategies

Author:

Kelly Deborah F.12ORCID,Jonaid G M123,Kaylor Liam124,Solares Maria J.124,Berry Samantha12,DiCecco Liza-Anastasia12,Dearnaley William12,Casasanta Michael12

Affiliation:

1. Department of Biomedical Engineering, Pennsylvania State University, University Park, PA 16802, USA

2. Center for Structural Oncology, Pennsylvania State University, University Park, PA 16802, USA

3. Bioinformatics and Genomics Graduate Program, Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA 16802, USA

4. Molecular, Cellular, and Integrative Biosciences Graduate Program, Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA 16802, USA

Abstract

As small protein assemblies and even small proteins are becoming more amenable to cryo-Electron Microscopy (EM) structural studies, it is important to consider the complementary dynamic information present in the data. Current computational strategies are limited in their ability to resolve minute differences among low molecular weight entities. Here, we demonstrate a new combinatorial approach to delineate flexible conformations among small proteins using real-space refinement applications. We performed a meta-analysis of structural data for the SARS CoV-2 Nucleocapsid (N) protein using a combination of rigid-body refinement and simulated annealing methods. For the N protein monomer, we determined three new flexible conformers with good stereochemistry and quantitative comparisons provided new evidence of their dynamic properties. A similar analysis performed for the N protein dimer showed only minor structural differences among the flexible models. These results suggested a more stable view of the N protein dimer than the monomer structure. Taken together, the new computational strategies can delineate conformational changes in low molecular weight proteins that may go unnoticed by conventional assessments. The results also suggest that small proteins may be further stabilized for structural studies through the use of solution components that limit the movement of external flexible regions.

Funder

Center for Structural Oncology, Huck Institutes of the Life Sciences, Pennsylvania State University

Publisher

MDPI AG

Subject

Electrical and Electronic Engineering,Mechanical Engineering,Control and Systems Engineering

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