7,676 research outputs found
Strong Selection Significantly Increases Epistatic Interactions in the Long-Term Evolution of a Protein
Epistatic interactions between residues determine a protein's adaptability
and shape its evolutionary trajectory. When a protein experiences a changed
environment, it is under strong selection to find a peak in the new fitness
landscape. It has been shown that strong selection increases epistatic
interactions as well as the ruggedness of the fitness landscape, but little is
known about how the epistatic interactions change under selection in the
long-term evolution of a protein. Here we analyze the evolution of epistasis in
the protease of the human immunodeficiency virus type 1 (HIV-1) using protease
sequences collected for almost a decade from both treated and untreated
patients, to understand how epistasis changes and how those changes impact the
long-term evolvability of a protein. We use an information-theoretic proxy for
epistasis that quantifies the co-variation between sites, and show that
positive information is a necessary (but not sufficient) condition that detects
epistasis in most cases. We analyze the "fossils" of the evolutionary
trajectories of the protein contained in the sequence data, and show that
epistasis continues to enrich under strong selection, but not for proteins
whose environment is unchanged. The increase in epistasis compensates for the
information loss due to sequence variability brought about by treatment, and
facilitates adaptation in the increasingly rugged fitness landscape of
treatment. While epistasis is thought to enhance evolvability via
valley-crossing early-on in adaptation, it can hinder adaptation later when the
landscape has turned rugged. However, we find no evidence that the HIV-1
protease has reached its potential for evolution after 9 years of adapting to a
drug environment that itself is constantly changing.Comment: 25 pages, 9 figures, plus Supplementary Material including
Supplementary Text S1-S7, Supplementary Tables S1-S2, and Supplementary
Figures S1-2. Version that appears in PLoS Genetic
Computational approaches to shed light on molecular mechanisms in biological processes
Computational approaches based on Molecular Dynamics simulations, Quantum Mechanical methods and 3D Quantitative Structure-Activity Relationships were employed by computational chemistry groups at the University of Milano-Bicocca to study biological processes at the molecular level. The paper reports the methodologies adopted and the results obtained on Aryl hydrocarbon Receptor and homologous PAS proteins mechanisms, the properties of prion protein peptides, the reaction pathway of hydrogenase and peroxidase enzymes and the defibrillogenic activity of tetracyclines. © Springer-Verlag 2007
Statistical Physics of Evolutionary Trajectories on Fitness Landscapes
Random walks on multidimensional nonlinear landscapes are of interest in many
areas of science and engineering. In particular, properties of adaptive
trajectories on fitness landscapes determine population fates and thus play a
central role in evolutionary theory. The topography of fitness landscapes and
its effect on evolutionary dynamics have been extensively studied in the
literature. We will survey the current research knowledge in this field,
focusing on a recently developed systematic approach to characterizing path
lengths, mean first-passage times, and other statistics of the path ensemble.
This approach, based on general techniques from statistical physics, is
applicable to landscapes of arbitrary complexity and structure. It is
especially well-suited to quantifying the diversity of stochastic trajectories
and repeatability of evolutionary events. We demonstrate this methodology using
a biophysical model of protein evolution that describes how proteins maintain
stability while evolving new functions
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