(629e) Resolution of the Minimum Free Energy Pathway of Integrin Activation Using Generative Modeling and Finite Temperature String Method

Understanding integrin activation is of large interest because of its central role in various cellular functions and in designing therapeutics targeting integrin.[1-5] However, accessing the full continuous conformations of integrin activation is challenging using experimental methods because of their transient nature and via all-atom molecular dynamics simulations because of the inordinate computational resources required as the system comprises more than a million atoms. To this end, we have previously developed a multi-scale simulation technique combining non-linear manifold learning and deep generative modeling methods to predict the full continuous activation conformations of integrin.[6] While this technique enabled access to the currently unknown continuous intermediate conformations of integrin activation, the thermodynamically favorable activation mechanism remains elusive.

In this work, our goal is to map the minimum free energy pathway and understand the mechanism of integrin activation by focusing on αIIbβ3 integrin, a platelet integrin whose malfunction can lead to bleeding disorders and cancer. For this, we employ finite temperature string method with conformations of the initial images generated by our generative modeling technique. We use the experimentally hypothesized integrin activation pathways to set the location of the initial string. In each string iteration, we perform all-atom molecular dynamics simulations with explicit water representation at biophysical conditions of each image in parallel to evolve the string. In our talk, we will present our generalizable multi-scale simulation technique along with the biophysical insights of integrin activation gained from resolving its minimum free energy activation pathway.

[1] Bidone TC, Polley A, Jin J, Driscoll T, Iwamoto DV, Calderwood DA, Schwartz MA, Voth GA. Coarse-grained simulation of full-length integrin activation. Biophysical journal. 2019 Mar 19;116(6):1000-10.

[2] Banno A, Ginsberg MH. Integrin activation. Biochemical Society Transactions. 2008 Apr 1;36(2):229-34.

[3] Zhang Y, Wang H. Integrin signalling and function in immune cells. Immunology. 2012 Apr;135(4):268-75.

[4] Goodman SL, Picard M. Integrins as therapeutic targets. Trends in pharmacological sciences. 2012 Jul 1;33(7):405-12.

[5] Tong D, Soley N, Kolasangiani R, Schwartz MA, Bidone TC. αIIbβ3 integrin intermediates: from molecular dynamics to adhesion assembly. Biophysical Journal. 2022 Dec 23.

[6] Dasetty S, Bidone TC, Ferguson AL. Data-driven prediction of αIIbβ3 integrin activation paths using manifold learning and deep generative modeling. Biophysical Journal. 2023 Dec 14.