The Rynkiewicz Lab

I am a protein crystallographer with extensive experience in computational structural analysis. My work over the years has encompassed a broad range of techniques, including protein crystallography, kinetic assays, organic synthesis, NMR and ultraviolet spectroscopy, small molecule structure-based drug design, epitope mapping of antibodies, and molecular dynamics calculations.

Current Research

Mechanism of tropomyosin activation probed by energy landscape analysis. Muscle contraction is regulated in part by tropomyosin. The tropomysosin molecules wrap around actin thin filaments in the sarcomere, and the position of the tropomyosin chain regulates the binding of myosin to the thin filament. The regulatory transitions of tropomyosin have been mapped out by a variety of techniques including negative stain and cryo electron microscopy and computational studies. However, the electron microscopy structures only provide a static picture of tropomyosin during regulation, any dynamic information is lost. Many cardiomyopathies derive their deleterious cardiovascular effects from mutations of tropomyosin. Presumably, these mutations alter the regulatory transitions of tropomyosin in subtle ways that lead to aberrant cardiac function. By studying the energy of tropomyosin at discreet locations on the actin filament for mutant and wild-type tropomyosins, we hope to learn the root causes of these cardiomyopathies and propose mechanisms by which they develop. (left) MD simulation of tropomyosin (green ribbon) as it moves across the actin filament (white surface) during relaxation of muscle. Proline 333 of actin is highlighted in red as a reference to show the regulatory motion of tropomyosin.

Previous Research

The innate immune system provides a first line response to inhaled pathogens, partly through the activities of the C-type lectin proteins surfactant protein-A and surfactant protein-D. Each surfactant protein has a unique function, and our structural work was aimed at learning the molecular mechanisms by which each protein performs its function in lung surfactant. For surfactant protein-D, we studied a mutant (D325A/R343V) that displayed a broader range and increased potency of efficacy against influenza virus strains. For surfactant protein-A, we created specific mutations to the calcium binding properties of the molecule that were able to incorporate some surfactant protein-D-like activities into surfactant protein-A. These studies help to understand the structural evolution of the specific activities of the two surfactant proteins. (below) Lipid membrane binding by SP-A simulated using MD simulations. SP-A (ribbon representation in magenta) diffuses and binds firmly to the membrane bilayer within 100ns and stayed bound for another 100ns.

Recent Publications

Lehman W, Moore JR, Campbell SG, Rynkiewicz MJ. (2019) The Effect of Tropomyosin Mutations on Actin-Tropomyosin Binding: In Search of Lost Time. Biophys J. 116(12):2275-2284. doi: 10.1016/j.bpj.2019.05.009. PubMed PMID: 31130236.

Patel D, Mez J, Vardarajan BN, Staley L, Chung J, Zhang X, Farrell JJ, Rynkiewicz MJ, Cannon-Albright LA, Teerlink CC, Stevens J, Corcoran C, Gonzalez Murcia JD, Lopez OL, Mayeux R, Haines JL, Pericak-Vance MA, Schellenberg G, Kauwe JSK, Lunetta KL, Farrer LA (2019) Alzheimer’s Disease Sequencing Project. Association of Rare Coding Mutations With Alzheimer Disease and Other Dementias Among Adults of European Ancestry. JAMA Netw Open. 2(3):e191350. doi: 10.1001/jamanetworkopen.2019.1350. PubMed PMID: 30924900; PubMed Central PMCID: PMC6450321.

Lehman W, Rynkiewicz MJ, Moore JR. (2019) A new twist on tropomyosin binding to actin filaments: perspectives on thin filament function, assembly and biomechanics. J Muscle Res Cell Motil. Feb 15. doi: 10.1007/s10974-019-09501-5. [Epub ahead of print] PubMed PMID: 30771202.

Kiani FA, Lehman W, Fischer S, Rynkiewicz MJ. (2019) Spontaneous transitions of actin-bound tropomyosin toward blocked and closed states. J Gen Physiol. 151(1):4-8. doi: 10.1085/jgp.201812188. Epub 2018 Nov 15. PubMed PMID: 30442774; PubMed Central PMCID: PMC6314389.

Lehman W, Li X, Kiani FA, Moore JR, Campbell SG, Fischer S, Rynkiewicz MJ. (2018) Precise Binding of Tropomyosin on Actin Involves Sequence-Dependent Variance in Coiled-Coil Twisting. Biophys J. 115(6):1082-1092. doi: 10.1016/j.bpj.2018.08.017. Epub 2018 Aug 18. PubMed PMID: 30195938; PubMed Central PMCID: PMC6139885.

van Eijk M, Rynkiewicz MJ, Khatri K, Leymarie N, Zaia J, White MR, Hartshorn KL, Cafarella TR, van Die I, Hessing M, Seaton BA, Haagsman HP. Lectin-mediated binding and sialoglycans of porcine surfactant protein D synergistically neutralize influenza A virus. (2018) J Biol Chem. 293(27):10646-10662. doi: 10.1074/jbc.RA117.001430. Epub 2018 May 16. PubMed PMID: 29769321; PubMed Central PMCID: PMC6036198.

Farman GP, Rynkiewicz MJ, Orzechowski M, Lehman W, Moore JR. (2018) HCM and DCM cardiomyopathy-linked α-tropomyosin mutations influence off-state stability and crossbridge interaction on thin filaments. Arch Biochem Biophys. 647:84-92. doi: 10.1016/j.abb.2018.04.002. Epub 2018 Apr 5. PubMed PMID: 29626422; PubMed Central PMCID: PMC5958618.

Rynkiewicz MJ, Prum T, Hollenberg S, Kiani FA, Fagnant PM, Marston SB, Trybus KM, Fischer S, Moore JR, Lehman W. Tropomyosin Must Interact Weakly with Actin to Effectively Regulate Thin Filament Function. Biophys J. 2017 Dec 5;113(11):2444-2451. doi: 10.1016/j.bpj.2017.10.004. PubMed PMID: 29211998; PubMed Central PMCID: PMC5768522.

Viswanathan MC, Schmidt W, Rynkiewicz MJ, Agarwal K, Gao J, Katz J, Lehman W, Cammarato A. (2017) Distortion of the Actin A-Triad Results in Contractile Disinhibition and Cardiomyopathy. Cell Rep. 20(11):2612-2625. doi: 10.1016/j.celrep.2017.08.070. PubMed PMID: 28903042; PubMed Central PMCID: PMC5902318.

Rynkiewicz MJ, Wu H, Cafarella TR, Nikolaidis NM, Head JF, Seaton BA, McCormack FX. (2017) Differential Ligand Binding Specificities of the Pulmonary Collectins Are Determined by the Conformational Freedom of a Surface Loop. Biochemistry. Aug 8; 56(31):4095-4105. PMID: 28719181.

Rynkiewicz MJ, Fischer S, Lehman W. (2016) The propensity for tropomyosin twisting in the presence and absence of F-actin. Arch Biochem Biophys. 2016 Nov 1; 609:51-58. PMID: 27663225.

Goh BC, Wu H, Rynkiewicz MJ, Schulten K, Seaton BA, McCormack FX. (2016) Elucidation of Lipid Binding Sites on Lung Surfactant Protein A Using X-ray Crystallography, Mutagenesis, and Molecular Dynamics Simulations. Biochemistry. 2016 Jul 5; 55(26):3692-701. PMID: 27324153.

Fischer S, Rynkiewicz MJ, Moore JR, Lehman W. (2016) Tropomyosin diffusion over actin subunits facilitates thin filament assembly. Struct Dyn. 2016 Jan 14; 3(1):012002. PMID: 26798831.

Rynkiewicz MJ, Schott V, Orzechowski M, Lehman W, Fischer S. (2015) Electrostatic interaction map reveals a new binding position for tropomyosin on F-actin. J Muscle Res Cell Motil. 2015 Dec; 36(6):525-33. PMID: 26286845

Links:

BU Profile
ResearchGate
PubMed

Contact Us

Michael Rynkiewicz, Ph.D.
Department of Pharmacology, Physiology & Biophysics
Chobanian & Avedisian School of Medicine
700 Albany St. W408D
Boston MA 02118-2526

Phone: (617) 358-8482
e-mail: rynkiemj@bu.edu