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A Molecular Dynamics Study of Reovirus Attachment Protein 1 Reveals Conformational Changes in 1 Structure

Andrea Cavalli ^* , Andrea E. Prota , Thilo Stehle , Terence S. Dermody , Maurizio Recanatini ^*, Gerd Folkers  and Leonardo Scapozza 

^* Department of Pharmaceutical Sciences, University of Bologna, Bologna, Italy; Department of Chemistry and Applied Biosciences, Eidgenössische Technische Hochschule, Zürich, Switzerland; Laboratory of Developmental Immunology and Renal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; and Departments of Pediatrics and Microbiology and Immunology and Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University School of Medicine, Nashville, Tennessee

Correspondence: Address reprint requests to Dr. Andrea Cavalli, Department of Pharmaceutical Sciences—University of Bologna, Via Belmeloro 6, I-40126 Bologna, Italy. Tel.: 39-051-209-9735; Fax: 39-051-209-9734; E-mail: andrea.cavalli{at}unibo.it. Or to Prof. Dr. Leonardo Scapozza, Department of Applied Biosciences—ETH, Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland. Tel.: 41-1-635-6036; Fax: 41-1-635-6084; E-mail: leonardo.scapozza{at}pharma.ethz.ch.

Molecular dynamics simulations were performed using the recently determined crystal structure of the reovirus attachment protein, 1. These studies were conducted to improve an understanding of two unique features of 1 structure: the protonation state of Asp³⁴⁵, which is buried in the 1 trimer interface, and the flexibility of the protein at a defined region below the receptor-binding head domain. Three copies of aspartic acids Asp³⁴⁵ and Asp³⁴⁶ cluster in a solvent-inaccessible and hydrophobic region at the 1 trimer interface. These residues are hypothesized to mediate conformational changes in 1 during viral attachment or cell entry. Our results indicate that protonation of Asp³⁴⁵ is essential to the integrity of the trimeric structure seen by x-ray crystallography, whereas deprotonation induces structural changes that destabilize the trimer interface. This finding was confirmed by electrostatic calculations using the finite difference Poisson-Boltzmann method. Earlier studies show that 1 can exist in retracted and extended conformations on the viral surface. Since protonated Asp³⁴⁵ is necessary to form a stable, extended trimer, our results suggest that protonation of Asp³⁴⁵ may allow for a structural transition from a partially detrimerized molecule to the fully formed trimer seen in the crystal structure. Additional studies were conducted to quantify the previously observed flexibility of 1 at a defined region below the receptor-binding head domain. Increased mobility was observed for three polar residues (Ser²⁹¹, Thr²⁹², and Ser²⁹³) located within an insertion between the second and third ß-spiral repeats of the crystallized portion of the 1 tail. These amino acids interact with water molecules of the solvent bulk and are responsible for oscillating movement of the head of 50° during 5 ns of simulations. This flexibility may facilitate viral attachment and also function in cell entry and disassembly. These findings provide new insights about the conformational dynamics of 1 that likely underlie the initiation of the reovirus infectious cycle.