Hydrophilic protein-protein interfaces constitute a major part of all protein-protein interfaces and are thus of great importance. However, the quantitative characterization of their association is still an ongoing challenge and the driving force behind their association remains poorly characterized. Here, we have addressed the association of hydrophilic proteins and the role of water by means of extensive molecular dynamics simulations in explicit water using three well studied protein complexes; Barnase-Barstar, cytochrome c-cytochrome c peroxidase, and the N-terminal domain of enzyme I-histidine-containing phosphocarrier. The one-dimensional free energy profiles obtained from umbrella sampling simulations are downhill or, in other words, barrierless. Using these one-dimensional free energy profiles, the computed standard free energies of binding are -12.7 ± 1.1 kcal/mol, -9.4 ± 0.7 kcal/mol, and -8.4 ± 1.9 kcal/mol that are in reasonable to very good agreement with the experimental values of -19.6 kcal/mol, -8.8 kcal/mol, and -7.8 kcal/mol. As expected, analysis of the confined water between the hydrophilic complex partners shows that the density and the orientational order parameter deviate noticeably from the bulk values, especially at close separations of the confining proteins.

The immune system is by definition multi-scale because it involves biochemical networks that regulate cell fates across cell boundaries, but also because immune cells communicate with each other by direct contact or through the secretion of local or systemic signals. Furthermore, tumor and immune cells communicate, and this interaction is affected by the tumor microenvironment. Altogether, the tumor-immunity interaction is a complex multi-scale biological system whose analysis requires a systemic view to succeed in developing efficient immunotherapies for cancer and immune-related diseases. In this review we discuss the necessity and the structure of a systems medicine approach for the design of anticancer immunotherapies. We support the idea that the approach must be a combination of algorithms and methods from bioinformatics and patient-data-driven mathematical models conceived to investigate the role of clinical interventions in the tumor-immunity interaction. For each step of the integrative approach proposed, we review the advancement with respect to the computational tools and methods available, but also successful case studies. We particularized our idea for the case of identifying novel tumor-associated antigens and therapeutic targets by integration of patient's immune and tumor profiling in case of aggressive melanoma.

Cellular phenotypes are established and controlled by complex and precisely orchestrated molecular networks. In cancer, mutations and dysregulations of multiple molecular factors perturb the regulation of these networks and lead to malignant transformation. High-throughput technologies are a valuable source of information to establish the complex molecular relationships behind the emergence of malignancy, but full exploitation of this massive amount of data requires bioinformatics tools that rely on network-based analyses. In this report we present the Virtual Melanoma Cell, an online tool developed to facilitate the mining and interpretation of high-throughput data on melanoma by biomedical researches. The platform is based on a comprehensive, manually generated and expert-validated regulatory map composed of signaling pathways important in malignant melanoma. The Virtual Melanoma Cell is a tool designed to accept, visualize and analyze user-generated datasets. It is available at: https://www.vcells.net/melanoma. To illustrate the utilization of the web platform and the regulatory map, we have analyzed a large publicly available dataset accounting for anti-PD1 immunotherapy treatment of malignant melanoma patients.

Dendritic cells (DCs) are professional antigen-presenting cells that induce and regulate adaptive immunity by presenting antigens to T cells. Due to their coordinative role in adaptive immune responses, DCs have been used as cell-based therapeutic vaccination against cancer. The capacity of DCs to induce a therapeutic immune response can be enhanced by re-wiring of cellular signalling pathways with microRNAs (miRNAs). Methods: Since the activation and maturation of DCs is controlled by an interconnected signalling network, we deploy an approach that combines RNA sequencing data and systems biology methods to delineate miRNA-based strategies that enhance DC-elicited immune responses. Results: Through RNA sequencing of IKKβ-matured DCs that are currently being tested in a clinical trial on therapeutic anti-cancer vaccination, we identified 44 differentially expressed miRNAs. According to a network analysis, most of these miRNAs regulate targets that are linked to immune pathways, such as cytokine and interleukin signalling. We employed a network topology-oriented scoring model to rank the miRNAs, analysed their impact on immunogenic potency of DCs, and identified dozens of promising miRNA candidates, with miR-15a and miR-16 as the top ones. The results of our analysis are presented in a database that constitutes a tool to identify DC-relevant miRNA-gene interactions with therapeutic potential ( https://www.synmirapy.net/dc-optimization ). Conclusions: Our approach enables the systematic analysis and identification of functional miRNA-gene interactions that can be experimentally tested for improving DC immunogenic potency.