Paulo Almeida

Introduction

I have worked on the biochemistry and biophysics of membranes since I was an undergraduate, in my home country of Portugal, with Winchil Vaz. In 1988, I came to the University of Virginia to get a PhD degree with Tom Thompson. If I were to choose the most important thing I learned from Tom it was not to be afraid of working on a problem I knew nothing about. In Virginia, I met Rod Biltonen, with whom I ended up doing post-doctoral research. Rod taught me to think about biochemical problems in terms of statistical thermodynamics. More than that, I learned that science is not about knowing facts but about how to think.

In the last 20 years, I have been interested lipid-lipid and peptide-lipid interactions in membranes. Recently, I have been especially interested in understanding peptide translocation across membranes by combining experimental physical methods with theoretical approaches, including analytical and computational methods.

Between 2018-2022, I served as chair of our department, in what turned out to be almost four years of crisis management. Two months after I became chair, Hurricane Florence made landfall in Wilmington and destroyed our departmental building along with much of its contents. Then, COVID-19 came. But we now have new labs in new buildings, and I am happy to have returned to my faculty role in teaching and research.

Lipid Interactions in Membranes

My curiosity regarding lipid interactions in membranes dates to my first paper on diffusion in membranes containing cholesterol. We still don’t really know how cholesterol interacts with other lipids and what its function in the membrane really is. I have used a statistical mechanical approach to understanding these interactions and interpret experimental data from fluorescence, calorimetry, and nearest-neighbor interactions, the latter in the course of an extensive collaboration with Steve Regen, from Lehigh University. I have tried to place a number of different investigations under a common conceptual understanding of what these interactions are, how strong they are, and what they mean for the organization and the thermodynamic properties of membranes.

Peptide-Lipid Interactions

For the past 15 years, most of my attention has been devoted to the interactions of peptides and lipids in membranes, in great part in collaboration with Antje Pokorny Almeida. We have studied the interactions between amphipathic helical peptides (cell-penetrating, antimicrobial, and cytolytic) and membranes. I have been especially interested in understanding the spontaneous translocation of amphipathic peptides across membranes. My approach has always been quantitative, combining thermodynamics, kinetics, analytical, and computational methods, with experimental physical methods to understand peptide interactions and translocation across membranes in model membrane systems of biological relevance. During 2012–2016, we discovered some of the rules that determine the ability of peptides to spontaneously translocate across membranes and showed that positively charged peptides can cross lipid bilayers, in a way governed only by the laws of thermodynamics. Now, that interest is combined with a long-standing interest in protein folding, applied β-hairpin peptides and they assemble to fold into membrane β-barrels.

Teaching

Beyond research, I have always been committed to the education of undergraduate students. In 2016, I wrote a book titled Proteins: Concepts in Biochemistry, published by Garland. The book was intended as a teaching instrument particularly geared to advanced undergraduate and beginning graduate students. I approach the subject of proteins from a conceptual point if view, connecting structure, evolution, thermodynamics, statistical mechanics, and kinetics

Selected Publications

  • Almeida, P.F.F., Vaz, W.L.C., and Thompson, T.E. (1992) Lateral diffusion in the liquid phases of dimyristoylphosphatidylcholine/cholesterol lipid bilayers: a free volume analysis. Biochemistry 31, 6739–6747.

  • Almeida, P.F.F., and A. Pokorny (2009). Mechanisms of antimicrobial, cytolytic, and cell-penetrating peptides: from kinetics to thermodynamics. Biochemistry 48, 8083–8093.

  • Wheaten, S.A., F.D.O. Ablan, B.L. Spaller, J.M. Trieu, and P.F. Almeida (2013). Translocation of cationic amphipathic peptides across the membranes of pure phospholipid giant vesicles. J. Am. Chem. Soc. 135, 16517–16525.

  • Almeida, P.F. (2019) How to Determine Lipid Interactions in Membranes from Experiment Through the Ising Model. Langmuir 35, 21–40.

  • Frazier, M.L., Wright, J.R., Pokorny, A., and Almeida, P.F.F. (2007) Investigation of domain formation in sphingomyelin/cholesterol/POPC mixtures by fluorescence resonance energy transfer and Monte Carlo simulations. Biophys. J. 92, 2422–2433.

  • Almeida, P.F.F. (2009) Thermodynamics of Lipid Interactions in Complex Bilayers. Biochim. Biophys. Acta 1788, 72–85.

  • Almeida, P.F. (2011) A simple thermodynamic model of the liquid-ordered state and the interactions between phospholipids and cholesterol. Biophys. J. 100, 420–429.

  • Kreutzberger, M.A., Tejada, E., Wang, Y., and Almeida, P.F. (2015). GUVs melt like LUVs: The large heat capacity of MLVs is not due to large size or small curvature. Biophys. J. 108, 2619–2622.

  • Kreutzberger, M.A., Pokorny, A., and Almeida, P.F. (2017) Daptomycin–phosphatidylglycerol domains in lipid membranes. Langmuir 33, 13669–13679.

  • Pokorny, A., Birkbeck, H., and Almeida, P.F.F. (2002) Mechanism and kinetics of δ-lysin interaction with phospholipid vesicles. Biochemistry 41, 11044–11056.

  • Yandek, L.E., Pokorny, A., Floren, A., Knoelke, K., Langel, U., and Almeida, P.F.F. (2007) Mechanism of the cell-penetrating peptide Tp10 permeation of lipid bilayers. Biophys. J. 92, 2434–2444.

  • Gregory, S.M., A. Cavenaugh, V. Journigan, A. Pokorny, and P.F.F. Almeida. (2008) A quantitative model for the all-or-none permeabilization of phospholipid vesicles by the antimicrobial peptide Cecropin A. Biophys. J. 94, 1667–1680.

  • Almeida, P.F.F., and A. Pokorny (2009). Mechanisms of antimicrobial, cytolytic, and cell-penetrating peptides: from kinetics to thermodynamics. Biochemistry 48, 8083–8093.

  • Wheaten, S.A., F.D.O. Ablan, B.L. Spaller, J.M. Trieu, and P.F. Almeida (2013) Translocation of cationic amphipathic peptides across the membranes of pure phospholipid giant vesicles. J. Am. Chem. Soc. 135, 16517–16525.

  • Ablan, F.D., Spaller, B.L., Abdo, K.I, and Almeida, P.F. (2016) Charge distribution fine-tunes the translocation of α-helical amphipathic peptides across membranes. Biophys J. 111, 1738–1749.


Books

  • Almeida, P.F. (2016). Proteins: Concepts in Biochemistry. Garland Science, New York, 2016, 432 pp.


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If you are interested in a research opportunity, get in touch: almeidap (at) uncw.edu