Physics Seminar: Hierarchical Modeling of Protein Folding and Aggregation
Dr. Patricia Soto, assistant professor of physics at Creighton University, will be on campus to present this seminar.
Proteins are at the heart of the molecular machinery that sustains the living cell. A wealth of evidence indicates that the inherent conformational motions of protein molecules are essential to their function. Indeed, fine-tuning of these conformational motions with the cell milieu, within a relatively narrow range of a few kBT, allows proteins to perform a vast variety of fundamental biological tasks across a broad range of time and length scales. Once proteins are synthesized in the ribosome as a linear chain of covalently linked amino acids, they self-organize into a biologically active three-dimensional structure. This efficient conformational search, optimized by evolution and regulated both by the specific sequence of amino acids and the cell environment, is known as “protein folding”. Under pathological conditions in the cell, however, some proteins are unable to fold to their functional state or to remain in their marginally stable folded conformation. They adopt, then, an alternate incorrectly folded structure that cannot be degraded by the cell. Clinical evidence associates this process of aggregation with a number of debilitating diseases such as Alzheimer’s, Parkinson’s, Huntington’s and spongiform encephalopathies. Quantitative description of the thermodynamics and kinetics of protein (mis)folding and aggregation would be possible, in principle, if the Hamiltonian describing the interactions between protein, solvent and surrounding molecules were solvable. In practice this is not feasible given the huge number of relevant degrees of freedom to consider. The quest is, thus, to characterize the molecular events that lead to protein (mis)folding and aggregation. In the talk I will discuss examples that illustrate the use of methods from computational statistical mechanics to tackle this challenging problem. As case studies I will refer to mechanisms of (mis)folding in Alzheimer’s and prion diseases.
For more information, contact Frank Bentrem (frank.bentrem@nwciowa.edu).
Proteins are at the heart of the molecular machinery that sustains the living cell. A wealth of evidence indicates that the inherent conformational motions of protein molecules are essential to their function. Indeed, fine-tuning of these conformational motions with the cell milieu, within a relatively narrow range of a few kBT, allows proteins to perform a vast variety of fundamental biological tasks across a broad range of time and length scales. Once proteins are synthesized in the ribosome as a linear chain of covalently linked amino acids, they self-organize into a biologically active three-dimensional structure. This efficient conformational search, optimized by evolution and regulated both by the specific sequence of amino acids and the cell environment, is known as “protein folding”. Under pathological conditions in the cell, however, some proteins are unable to fold to their functional state or to remain in their marginally stable folded conformation. They adopt, then, an alternate incorrectly folded structure that cannot be degraded by the cell. Clinical evidence associates this process of aggregation with a number of debilitating diseases such as Alzheimer’s, Parkinson’s, Huntington’s and spongiform encephalopathies. Quantitative description of the thermodynamics and kinetics of protein (mis)folding and aggregation would be possible, in principle, if the Hamiltonian describing the interactions between protein, solvent and surrounding molecules were solvable. In practice this is not feasible given the huge number of relevant degrees of freedom to consider. The quest is, thus, to characterize the molecular events that lead to protein (mis)folding and aggregation. In the talk I will discuss examples that illustrate the use of methods from computational statistical mechanics to tackle this challenging problem. As case studies I will refer to mechanisms of (mis)folding in Alzheimer’s and prion diseases.
For more information, contact Frank Bentrem (frank.bentrem@nwciowa.edu).
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