Ultradonut topology of the nuclear envelope

Mehdi Torbatia, Tanmay P. Leleb, and Ashutosh Agrawala,1

a
Department of Mechanical Engineering, University of Houston, Houston, TX 77204; and bDepartment of Chemical Engineering, University of Florida,
Gainesville, FL 32611

The nuclear envelope is a unique topological structure formed

by lipid membranes in eukaryotic cells. Unlike other membrane
structures, the nuclear envelope comprises two concentric membrane shells fused at numerous sites with toroid-shaped pores that
impart a geometric genus on the order of thousands. Despite the
intriguing architecture and vital biological functions of the nuclear
membranes, how they achieve and maintain such a unique arrangement remains unknown. Here, we used the theory of elasticity and differential geometry to analyze the equilibrium shape
and stability of this structure. Our results show that modest inand out-of-plane stresses present in the membranes not only can
define the pore geometry, but also provide a mechanism for destabilizing membranes beyond a critical size and set the stage for the
formation of new pores. Our results suggest a mechanism wherein
nanoscale buckling instabilities can define the global topology of a
nuclear envelope-like structure.
nuclear envelope

| lipid membranes | topology | buckling instability

he cell nucleus is bounded by two lipid bilayers arranged in

a unique geometry called the nuclear envelope. These two
bilayers are shaped into concentric spheres that are maintained
at a remarkably uniform spacing of 3050 nm (1), and yet are
fused together at thousands of pores (holes) at an average
spacing of 250500 nm from each other [based on areal
density measurements (24)]. At these pores, the membranes
locally take on a toroid shape with a radius of curvature on the
order of 20 nm (Fig. 1). Lipid structures such as vesicles,
spherocylinders (bacterial membranes), and biconcave discoids
(red blood cell membranes) are all closed structures with no
holes, and hence possess a zero genus (5) (Fig. 1). A donut, on
the other hand, is also a closed structure but has one hole, and as
a result has a genus of 1 (Fig. 1). If we fuse two donuts, we get a
shape with a genus of 2, and if we fuse thousands of donuts and
bend them to form a sphere, we obtain a nucleus-membranelike
structure (Fig. 1). This structure, therefore, can be thought of as
an ultradonut with a genus on the order of thousands. How the
two membranes assemble in a unique arrangement with such a
large number of local fusions is a fundamental question in both
physics and biology that is still unresolved (610). To seek an
answer to this puzzle, we ask three natural questions based on
the common notions in the field of membrane physics.
First, can membrane curvature-mediated interactions determine
optimal pore number and interpore separation? This principle has
been successfully used to predict the interactions of membraneembedded proteins and nanoparticles (1113). However, in the
case of nuclear envelope, Fig. 1C (14) shows that the curved
shapes of the membranes at the pores do not persist over interpore
length scales; The curvature memory of the membranes is lost
beyond 100 nm and they remain essentially flat in between the
pores. As a result, a pore does not sense the presence of other
pores in its vicinity via the membrane, suggesting that the curvature-mediated interactions by themselves cannot determine the
interpore separation, the critical length scale required to define
the genus.
Second, can the system energy provide an optimal pore number
and interpore separation? For a membrane, the system energy
comprises three contributions (15): (i) the elastic bending energy of
www.pnas.org/cgi/doi/10.1073/pnas.1604777113

the surface given by the well-known HelfrichCanham energy

(16, 17), which penalizes geometric deviation from a flat state;
(ii) the energy due to the in-plane stress that resists areal change;
and (iii) the energy due to the out-of-plane stress that resists
changes in volume (details are presented in Methods). We can
now consider two concentric bilayer spheres with an in-plane
stress and out-of-plane stress p connected with n pores at
equilibrium. Let us assume that the addition of each new pore
changes the bending energy by ep, area by ap, and volume by vp.
For noninteracting n pores (as discussed above), the system
energy is nep + ap p vp , minus the energy of the spheres
with no pores (a constant). Without invoking any specific
values of the parameters, we can draw three possible outcomes: (i ) ep + ap p vp > 0, which implies that the addition of each new pore increases the system energy and it is,
therefore, optimal to have zero pores. (ii) ep + ap p vp < 0,
which means that the addition of each new pore decreases the
system energy and it is, therefore, optimal to have the maximum
number of pores allowed by the surface area of the spheres; and
(iii) ep + ap p vp = 0, which suggests that system energy is
insensitive to the number of pores and the system, therefore, can
have an arbitrary number of pores. Therefore, all three outcomes
do not furnish a critical length scale that determines the genus of
nucleus membranes.
Third, can the nuclear pore complex (NPC), the massive protein structure housed at the pore sites, determine the pore spacing? The chronological sequence of pore formation and NPC
assembly has been experimentally observed in a study by Kiseleva
et al. (18). The study reveals that first an isolated pore is formed
from the fusion of membranes and next, NPC proteins assemble at
the pore site. Thus, pore nucleation precedes NPC assembly, and
NPCmembrane interaction is unlikely to be the determinant of
pore spacing.
Significance
Lipid membranes exhibit a variety of morphologies tailored
to perform specific functions of cells and their organelles. A
unique lipid structure is the nuclear envelope which houses the
genome and plays a vital role in genome organization and
signaling pathways. The nuclear envelope is composed of two
fused membranes with thousands of toroid-shaped pores
with extremely high curvatures, the origin of which remains
an open question in biology. Here, we show that the architecture of this ultradonut may be generated by nanoscale
buckling instabilities triggered by membrane stresses during
nuclei growth. Our findings may help understand the impact
of membrane mechanics on the geometry and the functionality of the nucleus and more generally, other double-membrane organelles in cells.
Author contributions: T.P.L. and A.A. designed research; M.T. performed research; M.T.,
T.P.L., and A.A. analyzed data; and T.P.L. and A.A. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
1

To whom correspondence should be addressed. Email: [email protected].

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.

1073/pnas.1604777113/-/DCSupplemental.

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Edited by David A. Weitz, Harvard University, Cambridge, MA, and approved August 2, 2016 (received for review March 23, 2016)

Fig. 1. Nuclear envelope and the topology. (A) Nuclear envelope with two concentric membrane spheres fused at thousands of sites with toroid-shaped pores.
(B) Key geometric parameters that define the nuclear envelope architecture. These include the pore diameter, bilayer separation, and the pore separation. The
forces and mechanisms that regulate this unique geometry are not yet understood. (C) Experimental image showing a section of the nuclear envelope with
nuclear pores labeled as NP lying in the same observed plane. Other NPs might be out of the plane of observation. [Scale bar, 500 nm (14).] The image shows the
uniform bilayer separation and the typical pore separation. Beyond 100 nm, the bilayers essentially become flat and lose the curvature memory associated with
the pore region. (D) Shapes exhibiting different genus: sphere has a genus of 0, donut has a genus of 1, and two fused donuts have a genus of 2.

In this paper, we investigate the local geometry and the stability of membranes in the presence of membrane stresses. Using
nonlinear computational modeling, we show that modest in- and
out-of-plane stresses can define a pore-like geometry and trigger
buckling instabilities that can lead to sites for fusion between two
bilayers. Whereas tensile in-plane stress confers remarkable robustness and is able to predict observed local pore geometries,
small values of compressive stress, along with modest out-of-plane
stress, destabilize the bilayer and trigger buckling instabilities. We
propose a mechanism by which local nanoscale instabilities define
a critical length scale and determine the observed global topology.
Results
We investigated the equilibrium shapes of a circular bilayer with
a preexisting pore of radius R = 42.5 nm [observed pore radius in
mammalian cells (19)]. We modeled the bilayer as an elastic and
axisymmetric 2D surface. The symmetry enables simulation of
just one curve (shown in yellow in Fig. 2; also shown is the resulting
3D surface of revolution) to compute the bilayer morphology. We
primarily focused our attention on the outer (upper) membrane as
the inner (lower) membrane is kinematically constrained due to its
connection with an underlying filamentous sheet (nuclear lamina).
We simulated the effects of the mechanical state of the membrane,
defined by the in-plane stress (, also called tension) and the outof-plane stress (p, also called pressure) on the bilayer geometry
(Fig. 2). Because the pore radius was prescribed, bilayer geometry
near and away from the pore is determined by a single parameter:
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the bilayer height (Fig. 2). The orthogonal curvatures in the circumferential and the meridional directions at the pore are given by
the inverse of the prescribed pore radius and the computed bilayer

Fig. 2. Simulated membrane geometry. (A) Because of axisymmetry, only

the curve in yellow was simulated. The solid of revolution was obtained by
revolving the curve around the vertical axis. (B) The simulated curve subjected to the in-plane and out-of-plane stresses. The arrows indicate the
positive directions of the in-plane and out-of-plane stresses. The boundary
conditions employed in the simulations are shown in Fig. S1.

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Fig. 3. Impact of in- and out-of plane stresses on membrane geometry. (A) Three-dimensional geometry of a bilayer with R = 500 nm, = 0.15 mN/m, and
p = 1.25 Pa. (B) The deflection response of bilayers with different radii R as a function of in-plane stress when subjected to critical out-of-plane stress pc . The
bilayers show initial expansion upon -reduction. However, they undergo snap-through buckling instability at critical c . (C) Three-dimensional geometry of a
buckled bilayer with R = 500 nm, = 0.0024 mN/m, and p = 1.25 Pa. (D) Two-dimensional geometry of an expanding bilayer for P = 0. The red curve is for =
0.04 mN/m and the blue curve is for = 0.06 mN/m. (E) Two-dimensional geometry of the buckled bilayer for P = 1.25 Pa. The red curve is for = 0.0005 mN/m
and the blue curve is for = 0.0024 mN/m.

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height. In addition to the stresses, we also examined the effect of

the bilayer size on the equilibrium shape. Fig. 3 shows a strong
influence of f, p, Rg on the bilayer geometry and stability and
reveals two key findings.
First, in the tension regime (positive -values), the bilayer
exhibits a remarkable uniform height away from the pore. Fig.
3A shows the 3D geometry of one such simulated bilayer
(R = 500 nm, = 0.15 mN/m, and p = 1.25 Pa) (see Fig. S2 for
more bilayer geometries). The bilayer height initially decreases
with the in-plane stress but becomes insensitive at higher inplane stress values (Fig. 3B). Moreover, for higher normal
stresses (parameter p), the bilayer height becomes highly insensitive to the in-plane stress. Collectively, these results show
that the experimentally observed half-separation between bilayers of 1525 nm can be achieved for a wide range of f, p, Rg
values. In addition, these simulations also show that bilayers can
maintain a uniform height over long distances in the tensile regime (Fig. S3).
Second, in the compression regime (negative -values), the
bilayer height drops precipitously below a threshold in-plane
stress at each of the chosen values of p and R (Fig. 3B). This drop
shows the presence of a buckling instability where the outer

bilayer moves toward the inner bilayer above a critical pressure

(pc) and below a critical negative in-plane stress (c); the pressures in Fig. 3B are the critical pressures. For example, Fig. 3C
shows the 3D geometry of a buckled bilayer with R = 500 nm,
= 0.0024 mN/m, and p = 1.25 Pa. This buckling instability is
similar to a snap-through buckling instability observed in columns, plates, and shells (20). If only the in-plane stress is present, the simulated curved bilayer always buckles outward owing
to the convex curvature at the pore. If p < pc, the bilayer continues to expand out and buckle outward for negative (compressive) in-plane stress. Thus, owing to the curvature at the
pore, a buckling instability that moves the membrane inward
uniquely requires the presence of a compressive normal stress.
The buckling response is, therefore, greatly influenced by the
pore geometry, as has been previously observed in the context of
short toroidal segments (21, 22). Fig. 3 D and E shows the
contrasting outward and inward buckling of a 500-nm-radius
bilayer for p = 0 and p = pc, respectively. Interestingly, for p > pc,
even tensile in-plane stress in the membrane inward can trigger
inward buckling (Figs. S4 and S5). These results show that two
separate bilayers can be brought together for fusion in a preexisting

Fig. 4. Ease of buckling depends on the bilayer size. (A) Critical out-of-plane stress (pc ) needed to buckle a bilayer inward as a function of the inverse of the bilayer
area (text adjacent to the data points shows the corresponding bilayer radius). The critical pressure undergoes a significant increase for R < 200 nm. (B) Critical in-plane
stress (c ) needed to buckle a bilayer inward as a function of the inverse of the bilayer area (text adjacent to the data points shows the corresponding bilayer radius).
The critical stress varies linearly with the inverse of the area. The slope of the curve is c 23=A ( is the bending modulus and A is the area of the simulated bilayer).
(C) The deflection response of bilayers with different radii R as a function of in-plane stress when subjected to p = 1.25 Pa. Bilayers with R 400 deform outward,
whereas bilayer with R = 500 buckle inward. The plot reveals the propensity of larger bilayers to undergo instability at minimal in- and out-of-plane stresses.

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1. Franke WW, Scheer U, Krohne G, Jarasch ED (1981) The nuclear envelope and the
architecture of the nuclear periphery. J Cell Biol 91(3 Pt 2):39s50s.
2. Belgareh N, Doye V (1997) Dynamics of nuclear pore distribution in nucleoporin
mutant yeast cells. J Cell Biol 136(4):747759.

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curved membrane system analyzed here, therefore, uniquely captures the combined role of the in- and out-of plane stresses on
membrane buckling. We note that the tendency to buckle outward
could in principle come from the curvature of the nucleus itself.
But, because the curvature of the nucleus is 1/500 nm, and is
orders of magnitude smaller than the pore curvature of 1/20 nm,
symmetry-breaking is likely dominated by the local pore geometry.
Discussion
The nuclear envelope is a unique lipid bilayer structure with an
intricate nanoscale architecture and vital biological functions
(26). Using simple arguments we showed that in- and out-ofplane stresses can give rise to the pore geometry and the geometric topology observed in cell nuclei. A minimal in-plane stress
of 0.0024 mN/m and an out-of plane stress of 1 Pa is sufficient to explain the geometry and the topology of the doublebilayer structure. As these stresses are much smaller than the
maximum stresses membranes can endure (2729), our findings
may be of value to understanding the nanoarchitecture of the
nuclear envelope. Because our model predicts a stable structure
over a wide range of tensile stresses, nuclei may be able to easily
adjust to the changes in nuclear stresses in a biological setting
and yet acquire and maintain their geometry (30).
Our study reveals that minimal compressive out-of-plane stress
in a bilayer can trigger inward buckling instabilities as long as the
in-plane stress is vanishingly small. For modest stresses, our study
predicts a critical interpore separation of 250500 nm. Bilayers
smaller than 250-nm radius are very stable, whereas bilayers
greater than 500-nm radius are highly unstable. As water can
freely pass through the NPCs, we expect the transmembrane
pressure across the two bilayers to be very small (nearly vanishing) (31). As shown in ref. 23, vesicle fusion leads to an inplane stress of 0.01 mN/m. If we invoke these physiological
stresses, the length scale proposed in this study emerges as a
natural outcome. A similar scale is observed in vivo for the
interpore distance in nuclei in mammalian cells, suggesting
perhaps that lipid membrane mechanics may be an important
contributor to these geometries. This is a major finding of our
analysis that provides a critical length scale and shows that the
critical length scale is a function of the mechanical state of the
nuclear membranes. As argued earlier, other common notions
such as membrane-mediated interactions and optimal system
energy cannot explain the optimal genus of a fused doublebilayer structure.
Historically, buckling instabilities have been a subject of much
interest. Leonhard Euler derived the celebrated Euler buckling
formula for slender columns in the mid-18th century and the
buckling of plates and shells was analyzed in the early 20th
century (20). In the last few decades, buckling instabilities have
been used to model and understand the force-deformation response of a wide variety of biological structures including DNA
(32), cytoskeletal filaments (3336), membranes (3741), white
blood cells (42), viruses (43), and tissues (4447). Here we present an example in which the buckling of curved membranes can
explain the ultradonut topology of the nuclear envelope. Because
intracellular mechanical stresses impact most membrane-bound
organelles, it would not be surprising if buckling instabilities
contribute to the geometry and the morphological remodeling of
other intracellular structures.
ACKNOWLEDGMENTS. This work was supported by National Science Foundation Grants CMMI 1437330 (to A.A.) and CMMI 1437395 (to T.P.L.); and NIH
Grants R01 EB014869 and R01 GM102486 (to T.P.L.).

3. DAngelo MA, Anderson DJ, Richard E, Hetzer MW (2006) Nuclear pores form de novo
from both sides of the nuclear envelope. Science 312(5772):440443.
4. Dultz E, Ellenberg J (2010) Live imaging of single nuclear pores reveals unique assembly kinetics and mechanism in interphase. J Cell Biol 191(1):1522.

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bilayerpore geometry by triggering buckling instability in one or

both of the bilayers (Fig. S6 and Movies S1S3).
The buckling response is extremely sensitive to the area of the
membrane in between the pores (bilayer size). Both c and pc
decrease with an increase in the bilayer size (Fig. 4 A and B). The
critical out-of-plane stress (pc) rapidly increases as the radius is
decreased below R = 250 nm. The critical in-plane stress (c, corresponding to p = pc), on the other hand, shows a linear variation
with the inverse of the area. The linear fit reveals that c 23=A
( is the bending modulus and A is the area of the simulated bilayer). These results indicate that the propensity for buckling depends significantly on the bilayer area in between adjacent pores.
Fig. 4C shows the contrasting stability of the bilayers at a modest
p = 1.25 Pa. For small interpore areas, the bilayer buckles outward
at negative in-plane stresses, whereas for larger area, it bends inward. These results suggest that interpore spacings significantly
larger than 500 nm should not exist because the bilayer is highly
vulnerable to even nearly vanishing values of in-plane and normal
compressive stresses. Consistent with these numerical findings, the
interpore spacing in mammalian nuclei is observed to be in the
range of 250500 nm. The proposed mechanism therefore provides a critical length scale and suggests that nanoscale buckling
instabilities can potentially define the global topology of the doublemembrane structure. Three important remarks are in order here.
First, it is conceivable that transient reductions in the in-plane
stress in nuclear membranes due to fusion of cytoplasmic vesicles
(18) can trigger buckling instabilities and set the stage for membrane fusion. Pioneering experimental and theoretical studies have
indeed established that lipid uptake can generate compressive inplane stress and trigger instabilities in planar membranes and
spherical vesicles (2325). The experimental study by Bassereau
and coworkers (23) reveals that lipid recruitment can generate a
compressive in-plane stress on the order of 0.01 mN/m in
spherical vesicles. This finding further supports our prediction that
bilayers with radius smaller than 250 nm should be less vulnerable
to buckling instabilities (Fig. 4B).
Second, because of the assumption of axisymmetry, our simulations predict a circular ring over which the two membranes meet
(Fig. 3C and Fig. S7). This suggests that a new pore can form
anywhere along this ring around a preexisting pore. Although the
exact location cannot be predicted, the radial separation between
the old and the new pores will be equal to the predicted critical
length scale. Furthermore, the presence of other preexisting pores
in the neighborhood will lead to similar circular rings around each
pore. As a result, the intersection of these fusion rings will likely
become hot spots for the creation of new pores (Fig. S7). In
addition, the propensity of these hot spots to undergo membrane
fusion could be further enhanced by aggregation of fusion proteins
facilitated by curvature gradients at these junction sites.
Third, the role of the critical pressure is to counter the tendency to deform outward and make the membrane nearly flat
(with a gentle bias toward inward deformation) (see the red
curves in Fig. 3 D and E). Once this geometry is achieved, the
membrane essentially responds as a planar membrane subjected
to the applied in-plane stress. This is evident in Fig. 3E. The
curved membrane in the pore region undergoes minimal deformation. The rest of the membrane undergoes deformation
about the highest point which maintains its horizontal angle
during the deformation. For these reasons, the highest point
essentially serves as a fixed (clamped) support for the rest of the
membrane. The interesting consequence is that the predicted
critical in-plane stress is the same as would be calculated for a
flat circular membrane with no curvature at the boundaries. The

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