BRIEF RESEARCH REPORT article
Front. Comput. Neurosci.
This article is part of the Research TopicSimulating Developmental NeurobiologyView all articles
Common characteristics of variants linked to autism spectrum disorder in the WAVE regulatory complex
Provisionally accepted
Song Xie1,2
Ke Zuo1*
Silvia De Rubeis3,4,5,6,7,8
Giorgio Bonollo9
Giorgio Colombo9Paolo Ruggerone10*
Paolo Carloni1,11,2*- 1Computational Biomedicine, Institute of Neuroscience and Medicine INM-9, Forschungszentrum Jülich GmbH, Jülich, Germany
- 2Department of Physics, RWTH Aachen University, Aachen, Germany
- 3Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, United States
- 4Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, United States
- 5The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, United States
- 6Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, United States
- 7Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States
- 8Alper Center for Neural Development and Regeneration, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, United States
- 9Dipartimento di Chimica, Università di Pavia, Via Taramelli 12, Pavia, Italy
- 10Department of Physics, University of Cagliari, Monserrato, Cagliari, Italy
- 11JARA Institute: Molecular Neuroscience and Imaging, Institute of Neuroscience and Medicine INM-11, Forschungszentrum Jülich GmbH, Jülich, Germany
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Six variants associated with autism spectrum disorder (ASD) abnormally activate the WASP-family Verprolin-homologous protein (WAVE) regulatory complex (WRC), a critical regulator of actin dynamics. This abnormal activation may contribute to the pathogenesis of this disorder. Using molecular dynamics (MD) simulations, we recently investigated the structural dynamics of wild-type (WT) WRC and R87C, A455P, and Q725R WRC disease-linked variants. Here, by extending MD simulations to I664M, E665K, and D724H WRC, we suggest that all of the mutations weaken the interactions and affect intra-complex allosteric communication between the WAVE1 active C-terminal region (ACR) and the rest of the complex. This might contribute to an abnormal complex activation, a hallmark of WRC-linked ASD. In addition, all mutants but I664M destabilize the ACR V-helix and increase the participation of ACR in large-scale movements. All these features may also abnormally influence the inactive WRC toward a dysfunctional state. We hypothesize that small-molecule ligands counteracting these effects may help restore normal WRC regulation in ASD-related variants.
Keywords: wave regulatory complex, Autism Spectrum Disorder, Missense variants, molecular dynamics, Cavity detection
Received: 12 Sep 2025; Accepted: 27 Oct 2025.
Copyright: © 2025 Xie, Zuo, De Rubeis, Bonollo, Colombo, Ruggerone and Carloni. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Ke Zuo, k.zuo@stimulate-ejd.eu
Paolo Ruggerone, paolo.ruggerone@unica.it
Paolo Carloni, p.carloni@fz-juelich.de
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