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Biomedical subjects

Andrew Pohorille

Publications and source records attributed to Andrew Pohorille.

9 recordsLinked to original sources
PubMed2006

Constructing explanatory process models from biological data and knowledge.

OBJECTIVE: We address the task of inducing explanatory models from observations and knowledge about candidate biological processes, using the illustrative problem of modeling photosynthesis regulation. METHODS: We cast both models and background knowledge in terms of processes that interact to account for behavior. We also describe IPM, an algorithm for inducing quantitative process models from such input. RESULTS: We demonstrate IPM's use both on photosynthesis and on a second domain, biochemical kinetics, reporting the models induced and their fit to observations. CONCLUSION: We consider the generality of our approach, discuss related research on biological modeling, and suggest directions for future work.

Algorithms↗
PubMed2005

Insights into the recognition and association of transmembrane alpha-helices. The free energy of alpha-helix dimerization in glycophorin A.

The free energy of alpha-helix dimerization of the transmembrane (TM) region of glycophorin A was estimated from a 125-ns molecular dynamics (MD) simulation in a membrane mimetic. The free energy profile was obtained by allowing the TM helical segments to diffuse reversibly along the reaction pathway. Partition of the potential of mean force into free energy components illuminates the critical steps of alpha-helix recognition and association. At large separations, the TM segments are pushed together by the solvent, allowing initial, but not necessarily native, interhelical interactions to occur. This early recognition stage precedes the formation of native contacts, which is accompanied by a tilt of the helices, characteristic of the dimeric structure. This step is primarily driven by the van der Waals helix-helix interactions. Free energy perturbation calculations of the L75A and I76A point mutations reveal a disruption in helix-helix association due to a loss of favorable dispersion interactions. Additional MD simulations of the native TM dimer and of a single alpha-helix confirm that, prior to association, individual alpha-helices are independently stable, in agreement with the "two-stage" model of integral membrane protein folding.

Amino Acid Sequence↗
PubMed2005

The origin and early evolution of membrane channels.

The origin and early evolution of ion channels are considered from the point of view that the transmembrane segments of membrane proteins are structurally quite simple and do not require specific sequences to fold. We argue that the transport of solute species, especially ions, required an early evolution of efficient transport mechanisms, and that the emergence of simple ion channels was protobiologically plausible. We also argue that, despite their simple structure, such channels could possess properties that, at the first sight, appear to require markedly greater complexity. These properties can be subtly modulated by local modifications to the sequence rather than global changes in molecular architecture. In order to address the evolution and development of ion channels, we focus on identifying those protein domains that are commonly associated with ion channel proteins and are conserved throughout the three main domains of life (Eukarya, Bacteria, and Archaea). We discuss the potassium-sodium-calcium superfamily of voltage-gated ion channels, mechanosensitive channels, porins, and ABC-transporters and argue that these families of membrane channels have sufficiently universal architectures that they can readily adapt to the diverse functional demands arising during evolution.

Evolution, Molecular↗
PubMed2004

Assessing the efficiency of free energy calculation methods.

The efficiencies of two recently developed methods for calculating free energy changes along a generalized coordinate in a system are discussed in the context of other, related approaches. One method is based on Jarzynski's identity [Phys. Rev. Lett. 78, 2690 (1997)]. The second method relies on thermodynamic integration of the average force and is called the adaptive biasing force method [Darve and Pohorille, J. Chem. Phys. 115, 9169 (2001)]. Both methods are designed such that the system evolves along the chosen coordinate(s) without experiencing free energy barriers and they require calculating the instantaneous, unconstrained force acting on this coordinate using the formula derived by Darve and Pohorille. Efficiencies are analyzed by comparing analytical estimates of statistical errors and by considering two numerical examples-internal rotation of hydrated 1,2-dichloroethane and transfer of fluoromethane across a water-hexane interface. The efficiencies of both methods are approximately equal in the first but not in the second case. During transfer of fluoromethane the system is easily driven away from equilibrium and, therefore, the performance of the method based on Jarzynski's identity is poor.

Journal Article↗
PubMed2003

Membrane peptides and their role in protobiological evolution.

How simple membrane peptides performed such essential protocellular functions as transport of ions and organic matter across membranes separating the interior of the cell from the environment, capture and utilization of energy, and transduction of environmental signals, is a key question in protobiological evolution. On the basis of detailed, molecular-level computer simulations we explain how these peptides fold at water-membrane interfaces, insert into membranes, self-assemble into higher-order structures and acquire functions. We have investigated the interfacial behavior and folding of several peptides built of leucine and glutamine residues and have demonstrated that many of them tend to adopt ordered structures. Further, we have studied the insertion of an alpha-helical peptide containing leucine (L) and serine (S) of the form (LSLLLSL)3 into a model membrane. The transmembrane state is metastable, and approximately 15 kcal mol(-1) is required to insert the peptide into the membrane. Investigations of dimers formed by (LSLLLSL)3 and glycophorin A demonstrate how the favorable free energy of helix association can offset the unfavorable free energy of insertion, leading to self-assembly of peptide helices in the membrane. An example of a self-assembled structure is the tetrameric transmembrane pore of the influenza virus M2 protein, which is an efficient and selective voltage-gated proton channel. Our simulations explain the gating mechanism and provide guidelines how to re-engineer the channel to act as a simple proton pump. In general, emergence of integral membrane proteins appears to be quite feasible and may be easier to envision than the emergence of water-soluble proteins.

Amino Acids↗
PubMed2003

Incorporating biological knowledge into evaluation of causal regulatory hypotheses.

Biological data can be scarce and costly to obtain. The small number of samples available typically limits statistical power and makes reliable inference of causal relations extremely difficult. However, we argue that statistical power can be increased substantially by incorporating prior knowledge and data from diverse sources. We present a Bayesian framework that combines information from different sources and we show empirically that this lets one make correct causal inferences with small sample sizes that otherwise would be impossible.

Algorithms↗
PubMed2002

Artificial cells: prospects for biotechnology.

A variety of techniques can now be used to alter the genome of a cell. Although these techniques are very powerful, they have limitations related to cost and efficiency of scale. Artificial cells designed for specific applications combine properties of biological systems such as nanoscale efficiency, self-organization and adaptability at relatively low cost. Individual components needed for such structures have already been developed, and now the main challenge is to integrate them in functional microscopic compartments. It will then become possible to design and construct communities of artificial cells that can perform different tasks related to therapeutic and diagnostic applications.

Animals↗
PubMed2002

Guiding revision of regulatory models with expression data.

BioLingua is a computational system designed to support biologists' efforts to construct models, make predictions, and interpret data. In this paper, we focus on the specific task of revising an initial model of gene regulation based on expression levels from gene microarrays. We describe BioLingua's formalism for representing process models, its method for predicting qualitative correlations from such models, and its use of data to constrain search through the space of revised models. We also report experimental results on revising a model of photosynthetic regulation in Cyanobacteria to better fit expression data for both wild and mutant strains, along with model mutilation studies designed to test our method's robustness. In closing, we discuss related work on representing, discovering, and revising biological models, after which we propose some directions for future research.

Computational Biology↗