Connecting dynamics to structural data from an array of diverse yet complementary experimental sources, all-atom molecular dynamics (MD) simulations permit the exploration of biological phenomena in unparalleled detail. We employed MD simulations and molecular modeling to investigate the dynamic properties of virus capsids, to determine the atomic structure of highly-flexible capsid domains, which could not be solved using a single experimental method, and to unravel the molecular mechanisms of host-pathogen interactions. Furthermore, we have recently integrated MD simulation into a de novo antibody design program to assess the binding and thermal stabilities of the designed antibodies and to identify antibodies with high binding affinity.
We investigated a retrovirus capsid in its immature, non-infectious state. For a retrovirus to be infectious, the immature retrovirus has to undergo maturation where the immature capsid proteins, also known as Gag, are cleaved proteolytically and then rearranged to form a mature capsid. Obtaining an atomic structure of the immature capsid has been elusive for many years. Recent advances in cryo-electron microscopy have yielded high resolution density maps and therefore enabled accurate computational modelings and simulations. We report the first atomic model of an immature Gag lattice, using Rous sarcoma virus (RSV) as the model system. The model includes an atomic model of a flexible domain called spacer peptide. The immature Gag lattice model was obtained using homology modeling and microsecond-long MD simulations and was tested via mutagenesis experiments in vitro. Upon obtaining the atomic structure of immature RSV lattice, we characterized the roles of key charged residues of RSV by simulating the wild type and mutant structures. We discovered a novel allosteric pathway that could explain how a mutation could suppress the detrimental effect of another mutation despite being 20 Angstroms apart. Read more here.
The human body has two types of immune systems to prevent and combat viral infection: innate and adaptive immune systems. Lung surfactant proteins are part of the innate immune system, and they act at the front-end of the host defense. Surfactant proteins A (SP-A) and D (SP-D) protect humans from bacterial infection and influenza A virus, respectively. Using structural information from X-ray crystallography, we probe the interactions between SP-D and influenza A virus at the atomic level. Our simulation results show that a double mutant of SP-D binds stronger to influenza A virus using a different binding loop than the wild type SP-D. Additionally, the lipid binding properties of SP-A were probed using MD simulations and mutational studies. We found a non-canonical lipid binding site with several critical binding features that involve cation-π interactions. Steered MD simulations also revealed that SP-A binds to bacterial lipid more tightly than lung surfactant. These results suggest that SP-A may transfer from surfactant to bacterial membranes to initiate its host defense functions. Read more here.
Antibodies are secreted by a type of white blood cell called B lymphocytes, which is an important component of the adaptive immune system. Antibodies identify and neutralize pathogens such as bacteria and viruses. Developing antibodies using solely experimental methods is a time-consuming process. Therefore, computational methods have been developed to design antibodies. However, most of these computational methods lack dynamic information during the design process as only static structures are considered. To generate antibodies with high binding affinity, we incorporated MD simulation into the antibody design workflow to account for the dynamic nature of the antigen-antibody interaction. The antibody design program with the improved workflow has successfully designed high-affinity antibodies to target a small, 12-residue-long peptide antigen, and the program is currently being used to design antibodies targeting a larger antigen, namely the Ebola glycoprotein.

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