Abstract

Molecular dynamics (MD) simulations have become a powerful and popular method for the study of protein allostery, the widespread phenomenon in which a stimulus at one site on a protein influences the properties of another site on the protein. By capturing the motions of a protein’s constituent atoms, simulations can enable the discovery of allosteric binding sites and the determination of the mechanistic basis for allostery. These results can provide a foundation for applications including rational drug design and protein engineering. Here, we provide an introduction to the investigation of protein allostery using molecular dynamics simulation. We emphasize the importance of designing simulations that include appropriate perturbations to the molecular system, such as the addition or removal of ligands or the application of mechanical force. We also demonstrate how the bidirectional nature of allostery—the fact that the two sites involved influence one another in a symmetrical manner—can facilitate such investigations. Through a series of case studies, we illustrate how these concepts have been used to reveal the structural basis for allostery in several proteins and protein complexes of biological and pharmaceutical interest.Revealing Atomic-Level Mechanisms of Protein Allostery with Molecular Dynamics SimulationsRevealing Atomic-Level Mechanisms of Protein Allostery with Molecular Dynamics Simulations Computer designed of a Safe and immunogenic pharmacophoric activator mimicking physicochemical properties of the MART-1 (26-35,27L), gp100 (209-217, 210M), and tyrosinase (368-376, 370D) inadjuvantwith PF-3512676 and GM-CSF with promising clinical outcome in metastatic melanoma using a new cluster of algorithms and a Ligand-Based Virtual Screening approach through a Support Vector and Information Fusion Bayesian Machine. The effectivenes of cancer vaccines in inducing CD8+Tcell responses remains a challenge, resulting in a need for testing more potent adjuvants. In previous clinical trials it has been determined the safetyand immunogenicity of vaccination against melanoma-related antigens employing MART-1,gp100, and tysosinase paptides combined with the TLR-9 agonist PF-3512676 and local GM-CSFin-oil emulsion.Using continuous monitoring of safety and a two-stage design for immunological efficacy, More than 20 immune-response evaluable patients were targetted. Vaccinations were given subcutaneously ondays 1 and 15 per cycle (1 cycle=28 days) for up to 13 cycles. Structure-based virtual screening of molecular compound libraries is a potentially powerful and inexpensive method for the discovery of novel lead compounds for drug development. That said, virtual screening is heavily dependent on detailed understanding of the tertiary or quaternary structure of the protein target of interest, including knowledge of the relevant binding pocket. Here, in Biogenea we have for the first time revealed Atomic-Level Computer designed Mechanisms of Protein Allostery with Molecular Dynamics Simulations on a Ligand-Based Virtual Screening approach through a Support Vector and Information Fusion Bayesian Machine of a Safe and immunogenic pharmacophoric activator mimicking MART-1 (26-35,27L), gp100 (209-217, 210M), and tyrosinase (368-376, 370D) with physicochemical PF-3512676 and GM-CSF adjuvant promising clinical properties in metastatic melanoma.

Keywords

Revealing Atomic-Level; Mechanisms of Protein; Allostery with Molecular Dynamics; Simulations Computer designed; Safe and immunogenic pharmacophoric activator; mimicking physicochemical properties; MART-1 (26-35,27L), gp100 (209-217, 210M), tyrosinase (368-376, 370D), PF-3512676; GM-CSF; metastatic melanoma; cluster of algorithms; Ligand-Based Virtual Screening approach; Support Vector; Information Fusion Bayesian Machine.