Molecular dynamics of the immune checkpoint Programmed Cell Death Protein I, PD1: Conformational changes of the BCloop upon binding of the ligand PDL1 and the monoclonal antibody nivolumab The immune checkpoint receptor programmed cell death protein I (PD1) has been identified as a key target in immunotherapy. PD1 reduces the risk of autoimmunity by inducing apoptosis in antigenspecific T cells upon interaction with programmed cell death protein ligand I (PDL1). Various cancer types overexpress PDL1 to evade the immune system by inducing apoptosis in tumorspecific CD8 T cells. The clinically used blocking antibody nivolumab binds to PD1 and inhibits the immunosuppressive interaction with PDL1. Even though PD1 is already used as a drug target the exact mechanism of the receptor is still unclear. For instance, the signal transduction from the extra to the intracellular domain of PD1 is still a matter of debate. It is hypothesized that the signal transduction is based on an active conformation of PD1. Here we present the results of the first molecular dynamics simulations of PD1 with a complete extracellular domain with a focus on the role of the BCloop of PD1 upon binding PDL1 or nivolumab. We could identify that the BCloop can form three conformations. Nivolumab binds to the BCloop according to the conformational selection model whereas PDL1 induces allosterically a conformational change of the BCloop. Based on the structural differences of the BCloop a signal transduction based on active conformation cannot be ruled out.

Computational Analysis of Structural Dynamics of EGFR and its Mutants Nonsmall cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) is a major cause of death worldwide. Tyrosine kinase inhibitors (TKIs) have been developed to target the EGFR, stop the downstream signaling and the tumor growth. Despite of initial good results, drug resistance is developed after one year due to a secondary mutation. The L858R, T790M mutation and their combination change the conformational redistribution of EGFR. To combat drug resistance caused by the T790M mutation, AZD9291 third generation drug was approved by the food and drug administration agency, FDA, USA. However, resistance to AZD9291 is developed due to C797S mutation. In this paper, we investigate the drug resistance due to these genomic variations. We perform molecular dynamics (MD) simulation for EGFR, EGFR with L858R single point mutation, EGFR with L858R and T790M double point mutation and EGFR with L858R, T790M and C797S triple point mutation. We apply principal component analysis PCA and clustering to the atomic trajectories of EGFR and its mutants and extract the dominant motions. The first PC captures 29.04%, 51.17% 53.79% and 51.67% variance in WT, L858R, T790M and C797S mutants, respectively. First 20 PCs are used to explain the dynamics of the system, that captures about 90% of the variance in the system. This shows that the mutation increases the variance which leads to structural and dynamical changes and can be one of the reasons for the drug resistance. Our results provide new insights to the conformational dynamics and structural changes in EGFR and its mutants, that can be helpful for understanding the drug resistance mechanism and designing future therapies for NSCLC patients.